Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors
Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cel...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Terzic, Julie [verfasserIn] Abu el Maaty, Mohamed A [verfasserIn] Lutzing, Régis [verfasserIn] Vincent, Alexandre [verfasserIn] El Bizri, Rana [verfasserIn] Jung, Matthieu [verfasserIn] Keime, Céline [verfasserIn] Metzger, Daniel [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2023 |
|---|
| Schlagwörter: |
|---|
| Anmerkung: |
© The Author(s) 2023 |
|---|
| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 15(2023), 6 vom: 18. Apr. |
|---|---|
| Übergeordnetes Werk: |
volume:15 ; year:2023 ; number:6 ; day:18 ; month:04 |
| Links: |
|---|
| DOI / URN: |
10.15252/emmm.202217209 |
|---|
| Katalog-ID: |
SPR058184996 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR058184996 | ||
| 003 | DE-627 | ||
| 005 | 20241030065043.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 241030s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.15252/emmm.202217209 |2 doi | |
| 035 | |a (DE-627)SPR058184996 | ||
| 035 | |a (SPR)emmm.202217209-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Terzic, Julie |e verfasserin |0 (orcid)0000-0002-9464-2041 |4 aut | |
| 245 | 1 | 0 | |a Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © The Author(s) 2023 | ||
| 520 | |a Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. | ||
| 520 | |a Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. | ||
| 520 | |a Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. | ||
| 650 | 4 | |a castration‐resistant prostate cancer |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a genetically‐engineered mice |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a HIF1A |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a PTEN |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a single‐cell RNA sequencing |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Abu el Maaty, Mohamed A |e verfasserin |0 (orcid)0000-0002-8760-6376 |4 aut | |
| 700 | 1 | |a Lutzing, Régis |e verfasserin |0 (orcid)0000-0002-9927-1825 |4 aut | |
| 700 | 1 | |a Vincent, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a El Bizri, Rana |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Matthieu |e verfasserin |4 aut | |
| 700 | 1 | |a Keime, Céline |e verfasserin |0 (orcid)0000-0001-7604-3814 |4 aut | |
| 700 | 1 | |a Metzger, Daniel |e verfasserin |0 (orcid)0000-0002-5555-046X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t EMBO Molecular Medicine |d Nature Publishing Group UK, 2023 |g 15(2023), 6 vom: 18. Apr. |w (DE-627)594772761 |w (DE-600)2485479-7 |x 1757-4684 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2023 |g number:6 |g day:18 |g month:04 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.15252/emmm.202217209 |m X:SPRINGER |x Resolving-System |z kostenfrei |3 Volltext |
| 912 | |a SYSFLAG_0 | ||
| 912 | |a GBV_SPRINGER | ||
| 912 | |a GBV_ILN_20 | ||
| 912 | |a GBV_ILN_22 | ||
| 912 | |a GBV_ILN_23 | ||
| 912 | |a GBV_ILN_24 | ||
| 912 | |a GBV_ILN_31 | ||
| 912 | |a GBV_ILN_39 | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_60 | ||
| 912 | |a GBV_ILN_62 | ||
| 912 | |a GBV_ILN_63 | ||
| 912 | |a GBV_ILN_65 | ||
| 912 | |a GBV_ILN_69 | ||
| 912 | |a GBV_ILN_72 | ||
| 912 | |a GBV_ILN_73 | ||
| 912 | |a GBV_ILN_74 | ||
| 912 | |a GBV_ILN_95 | ||
| 912 | |a GBV_ILN_105 | ||
| 912 | |a GBV_ILN_110 | ||
| 912 | |a GBV_ILN_151 | ||
| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_171 | ||
| 912 | |a GBV_ILN_206 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_224 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_636 | ||
| 912 | |a GBV_ILN_2001 | ||
| 912 | |a GBV_ILN_2003 | ||
| 912 | |a GBV_ILN_2004 | ||
| 912 | |a GBV_ILN_2005 | ||
| 912 | |a GBV_ILN_2006 | ||
| 912 | |a GBV_ILN_2007 | ||
| 912 | |a GBV_ILN_2009 | ||
| 912 | |a GBV_ILN_2010 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
| 912 | |a GBV_ILN_2020 | ||
| 912 | |a GBV_ILN_2021 | ||
| 912 | |a GBV_ILN_2025 | ||
| 912 | |a GBV_ILN_2026 | ||
| 912 | |a GBV_ILN_2027 | ||
| 912 | |a GBV_ILN_2034 | ||
| 912 | |a GBV_ILN_2037 | ||
| 912 | |a GBV_ILN_2038 | ||
| 912 | |a GBV_ILN_2044 | ||
| 912 | |a GBV_ILN_2048 | ||
| 912 | |a GBV_ILN_2049 | ||
| 912 | |a GBV_ILN_2050 | ||
| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2057 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2068 | ||
| 912 | |a GBV_ILN_2088 | ||
| 912 | |a GBV_ILN_2093 | ||
| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2108 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2111 | ||
| 912 | |a GBV_ILN_2118 | ||
| 912 | |a GBV_ILN_2122 | ||
| 912 | |a GBV_ILN_2129 | ||
| 912 | |a GBV_ILN_2143 | ||
| 912 | |a GBV_ILN_2144 | ||
| 912 | |a GBV_ILN_2147 | ||
| 912 | |a GBV_ILN_2148 | ||
| 912 | |a GBV_ILN_2152 | ||
| 912 | |a GBV_ILN_2153 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2232 | ||
| 912 | |a GBV_ILN_2336 | ||
| 912 | |a GBV_ILN_2470 | ||
| 912 | |a GBV_ILN_2507 | ||
| 912 | |a GBV_ILN_2548 | ||
| 912 | |a GBV_ILN_4012 | ||
| 912 | |a GBV_ILN_4029 | ||
| 912 | |a GBV_ILN_4035 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4046 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4116 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4155 | ||
| 912 | |a GBV_ILN_4242 | ||
| 912 | |a GBV_ILN_4246 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4251 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4311 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4314 | ||
| 912 | |a GBV_ILN_4315 | ||
| 912 | |a GBV_ILN_4317 | ||
| 912 | |a GBV_ILN_4318 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4326 | ||
| 912 | |a GBV_ILN_4328 | ||
| 912 | |a GBV_ILN_4333 | ||
| 912 | |a GBV_ILN_4334 | ||
| 912 | |a GBV_ILN_4335 | ||
| 912 | |a GBV_ILN_4336 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4367 | ||
| 912 | |a GBV_ILN_4393 | ||
| 912 | |a GBV_ILN_4598 | ||
| 912 | |a GBV_ILN_4700 | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2023 |e 6 |b 18 |c 04 | ||
| author_variant |
j t jt e m m a a emma emmaa r l rl a v av b r e br bre m j mj c k ck d m dm |
|---|---|
| matchkey_str |
article:17574684:2023----::yoiidcbeatraniiinvroecsrtors |
| hierarchy_sort_str |
2023 |
| publishDate |
2023 |
| allfields |
10.15252/emmm.202217209 doi (DE-627)SPR058184996 (SPR)emmm.202217209-e DE-627 ger DE-627 rakwb eng Terzic, Julie verfasserin (orcid)0000-0002-9464-2041 aut Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 Abu el Maaty, Mohamed A verfasserin (orcid)0000-0002-8760-6376 aut Lutzing, Régis verfasserin (orcid)0000-0002-9927-1825 aut Vincent, Alexandre verfasserin aut El Bizri, Rana verfasserin aut Jung, Matthieu verfasserin aut Keime, Céline verfasserin (orcid)0000-0001-7604-3814 aut Metzger, Daniel verfasserin (orcid)0000-0002-5555-046X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 15(2023), 6 vom: 18. Apr. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:15 year:2023 number:6 day:18 month:04 https://dx.doi.org/10.15252/emmm.202217209 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 15 2023 6 18 04 |
| spelling |
10.15252/emmm.202217209 doi (DE-627)SPR058184996 (SPR)emmm.202217209-e DE-627 ger DE-627 rakwb eng Terzic, Julie verfasserin (orcid)0000-0002-9464-2041 aut Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 Abu el Maaty, Mohamed A verfasserin (orcid)0000-0002-8760-6376 aut Lutzing, Régis verfasserin (orcid)0000-0002-9927-1825 aut Vincent, Alexandre verfasserin aut El Bizri, Rana verfasserin aut Jung, Matthieu verfasserin aut Keime, Céline verfasserin (orcid)0000-0001-7604-3814 aut Metzger, Daniel verfasserin (orcid)0000-0002-5555-046X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 15(2023), 6 vom: 18. Apr. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:15 year:2023 number:6 day:18 month:04 https://dx.doi.org/10.15252/emmm.202217209 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 15 2023 6 18 04 |
| allfields_unstemmed |
10.15252/emmm.202217209 doi (DE-627)SPR058184996 (SPR)emmm.202217209-e DE-627 ger DE-627 rakwb eng Terzic, Julie verfasserin (orcid)0000-0002-9464-2041 aut Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 Abu el Maaty, Mohamed A verfasserin (orcid)0000-0002-8760-6376 aut Lutzing, Régis verfasserin (orcid)0000-0002-9927-1825 aut Vincent, Alexandre verfasserin aut El Bizri, Rana verfasserin aut Jung, Matthieu verfasserin aut Keime, Céline verfasserin (orcid)0000-0001-7604-3814 aut Metzger, Daniel verfasserin (orcid)0000-0002-5555-046X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 15(2023), 6 vom: 18. Apr. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:15 year:2023 number:6 day:18 month:04 https://dx.doi.org/10.15252/emmm.202217209 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 15 2023 6 18 04 |
| allfieldsGer |
10.15252/emmm.202217209 doi (DE-627)SPR058184996 (SPR)emmm.202217209-e DE-627 ger DE-627 rakwb eng Terzic, Julie verfasserin (orcid)0000-0002-9464-2041 aut Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 Abu el Maaty, Mohamed A verfasserin (orcid)0000-0002-8760-6376 aut Lutzing, Régis verfasserin (orcid)0000-0002-9927-1825 aut Vincent, Alexandre verfasserin aut El Bizri, Rana verfasserin aut Jung, Matthieu verfasserin aut Keime, Céline verfasserin (orcid)0000-0001-7604-3814 aut Metzger, Daniel verfasserin (orcid)0000-0002-5555-046X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 15(2023), 6 vom: 18. Apr. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:15 year:2023 number:6 day:18 month:04 https://dx.doi.org/10.15252/emmm.202217209 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 15 2023 6 18 04 |
| allfieldsSound |
10.15252/emmm.202217209 doi (DE-627)SPR058184996 (SPR)emmm.202217209-e DE-627 ger DE-627 rakwb eng Terzic, Julie verfasserin (orcid)0000-0002-9464-2041 aut Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 Abu el Maaty, Mohamed A verfasserin (orcid)0000-0002-8760-6376 aut Lutzing, Régis verfasserin (orcid)0000-0002-9927-1825 aut Vincent, Alexandre verfasserin aut El Bizri, Rana verfasserin aut Jung, Matthieu verfasserin aut Keime, Céline verfasserin (orcid)0000-0001-7604-3814 aut Metzger, Daniel verfasserin (orcid)0000-0002-5555-046X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 15(2023), 6 vom: 18. Apr. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:15 year:2023 number:6 day:18 month:04 https://dx.doi.org/10.15252/emmm.202217209 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 15 2023 6 18 04 |
| language |
English |
| source |
Enthalten in EMBO Molecular Medicine 15(2023), 6 vom: 18. Apr. volume:15 year:2023 number:6 day:18 month:04 |
| sourceStr |
Enthalten in EMBO Molecular Medicine 15(2023), 6 vom: 18. Apr. volume:15 year:2023 number:6 day:18 month:04 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
castration‐resistant prostate cancer genetically‐engineered mice HIF1A PTEN single‐cell RNA sequencing |
| isfreeaccess_bool |
true |
| container_title |
EMBO Molecular Medicine |
| authorswithroles_txt_mv |
Terzic, Julie @@aut@@ Abu el Maaty, Mohamed A @@aut@@ Lutzing, Régis @@aut@@ Vincent, Alexandre @@aut@@ El Bizri, Rana @@aut@@ Jung, Matthieu @@aut@@ Keime, Céline @@aut@@ Metzger, Daniel @@aut@@ |
| publishDateDaySort_date |
2023-04-18T00:00:00Z |
| hierarchy_top_id |
594772761 |
| id |
SPR058184996 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058184996</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241030065043.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241030s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202217209</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058184996</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202217209-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Terzic, Julie</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9464-2041</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2023</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">castration‐resistant prostate cancer</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">genetically‐engineered mice</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">HIF1A</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PTEN</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">single‐cell RNA sequencing</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Abu el Maaty, Mohamed A</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-8760-6376</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lutzing, Régis</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9927-1825</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Vincent, Alexandre</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">El Bizri, Rana</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Jung, Matthieu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Keime, Céline</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-7604-3814</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Metzger, Daniel</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5555-046X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">EMBO Molecular Medicine</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">15(2023), 6 vom: 18. Apr.</subfield><subfield code="w">(DE-627)594772761</subfield><subfield code="w">(DE-600)2485479-7</subfield><subfield code="x">1757-4684</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:15</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:6</subfield><subfield code="g">day:18</subfield><subfield code="g">month:04</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.15252/emmm.202217209</subfield><subfield code="m">X:SPRINGER</subfield><subfield code="x">Resolving-System</subfield><subfield code="z">kostenfrei</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_0</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_72</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_224</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_636</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2004</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2006</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2025</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2027</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2034</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2038</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2044</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2048</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2049</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2050</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2056</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2057</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2061</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2068</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2088</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2093</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2106</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2129</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2144</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2147</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2148</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2190</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2232</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2470</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2507</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2548</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4029</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4046</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4116</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4155</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4242</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4311</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4314</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4315</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4317</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4318</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4326</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4328</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4333</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4334</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4335</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4393</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4598</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">15</subfield><subfield code="j">2023</subfield><subfield code="e">6</subfield><subfield code="b">18</subfield><subfield code="c">04</subfield></datafield></record></collection>
|
| author |
Terzic, Julie |
| spellingShingle |
Terzic, Julie misc castration‐resistant prostate cancer misc genetically‐engineered mice misc HIF1A misc PTEN misc single‐cell RNA sequencing Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| authorStr |
Terzic, Julie |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)594772761 |
| format |
electronic Article |
| delete_txt_mv |
keep |
| author_role |
aut aut aut aut aut aut aut aut |
| collection |
springer |
| remote_str |
true |
| illustrated |
Not Illustrated |
| issn |
1757-4684 |
| topic_title |
Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors castration‐resistant prostate cancer (dpeaa)DE-He213 genetically‐engineered mice (dpeaa)DE-He213 HIF1A (dpeaa)DE-He213 PTEN (dpeaa)DE-He213 single‐cell RNA sequencing (dpeaa)DE-He213 |
| topic |
misc castration‐resistant prostate cancer misc genetically‐engineered mice misc HIF1A misc PTEN misc single‐cell RNA sequencing |
| topic_unstemmed |
misc castration‐resistant prostate cancer misc genetically‐engineered mice misc HIF1A misc PTEN misc single‐cell RNA sequencing |
| topic_browse |
misc castration‐resistant prostate cancer misc genetically‐engineered mice misc HIF1A misc PTEN misc single‐cell RNA sequencing |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
cr |
| hierarchy_parent_title |
EMBO Molecular Medicine |
| hierarchy_parent_id |
594772761 |
| hierarchy_top_title |
EMBO Molecular Medicine |
| isfreeaccess_txt |
true |
| familylinks_str_mv |
(DE-627)594772761 (DE-600)2485479-7 |
| title |
Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| ctrlnum |
(DE-627)SPR058184996 (SPR)emmm.202217209-e |
| title_full |
Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| author_sort |
Terzic, Julie |
| journal |
EMBO Molecular Medicine |
| journalStr |
EMBO Molecular Medicine |
| lang_code |
eng |
| isOA_bool |
true |
| recordtype |
marc |
| publishDateSort |
2023 |
| contenttype_str_mv |
txt |
| author_browse |
Terzic, Julie Abu el Maaty, Mohamed A Lutzing, Régis Vincent, Alexandre El Bizri, Rana Jung, Matthieu Keime, Céline Metzger, Daniel |
| container_volume |
15 |
| format_se |
Elektronische Aufsätze |
| author-letter |
Terzic, Julie |
| doi_str_mv |
10.15252/emmm.202217209 |
| normlink |
(ORCID)0000-0002-9464-2041 (ORCID)0000-0002-8760-6376 (ORCID)0000-0002-9927-1825 (ORCID)0000-0001-7604-3814 (ORCID)0000-0002-5555-046X |
| normlink_prefix_str_mv |
(orcid)0000-0002-9464-2041 (orcid)0000-0002-8760-6376 (orcid)0000-0002-9927-1825 (orcid)0000-0001-7604-3814 (orcid)0000-0002-5555-046X |
| author2-role |
verfasserin |
| title_sort |
hypoxia‐inducible factor 1a inhibition overcomes castration resistance of prostate tumors |
| title_auth |
Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| abstract |
Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. © The Author(s) 2023 |
| abstractGer |
Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. © The Author(s) 2023 |
| abstract_unstemmed |
Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. © The Author(s) 2023 |
| collection_details |
SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 |
| container_issue |
6 |
| title_short |
Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors |
| url |
https://dx.doi.org/10.15252/emmm.202217209 |
| remote_bool |
true |
| author2 |
Abu el Maaty, Mohamed A Lutzing, Régis Vincent, Alexandre El Bizri, Rana Jung, Matthieu Keime, Céline Metzger, Daniel |
| author2Str |
Abu el Maaty, Mohamed A Lutzing, Régis Vincent, Alexandre El Bizri, Rana Jung, Matthieu Keime, Céline Metzger, Daniel |
| ppnlink |
594772761 |
| mediatype_str_mv |
c |
| isOA_txt |
true |
| hochschulschrift_bool |
false |
| doi_str |
10.15252/emmm.202217209 |
| up_date |
2024-10-30T14:10:26.051Z |
| _version_ |
1814348353821999104 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058184996</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241030065043.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241030s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202217209</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058184996</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202217209-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Terzic, Julie</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9464-2041</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2023</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of $ Pten^{(i)pe−/−} $ mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of $ Pten^{(i)pe−/−} $ mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">castration‐resistant prostate cancer</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">genetically‐engineered mice</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">HIF1A</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PTEN</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">single‐cell RNA sequencing</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Abu el Maaty, Mohamed A</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-8760-6376</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lutzing, Régis</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9927-1825</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Vincent, Alexandre</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">El Bizri, Rana</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Jung, Matthieu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Keime, Céline</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-7604-3814</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Metzger, Daniel</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5555-046X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">EMBO Molecular Medicine</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">15(2023), 6 vom: 18. Apr.</subfield><subfield code="w">(DE-627)594772761</subfield><subfield code="w">(DE-600)2485479-7</subfield><subfield code="x">1757-4684</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:15</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:6</subfield><subfield code="g">day:18</subfield><subfield code="g">month:04</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.15252/emmm.202217209</subfield><subfield code="m">X:SPRINGER</subfield><subfield code="x">Resolving-System</subfield><subfield code="z">kostenfrei</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_0</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_72</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_224</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_636</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2004</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2006</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2025</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2027</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2034</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2038</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2044</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2048</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2049</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2050</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2056</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2057</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2061</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2068</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2088</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2093</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2106</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2129</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2144</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2147</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2148</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2190</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2232</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2470</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2507</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2548</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4029</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4046</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4116</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4155</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4242</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4311</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4314</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4315</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4317</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4318</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4326</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4328</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4333</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4334</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4335</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4393</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4598</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">15</subfield><subfield code="j">2023</subfield><subfield code="e">6</subfield><subfield code="b">18</subfield><subfield code="c">04</subfield></datafield></record></collection>
|
| score |
7.400923 |