KRAS signaling in malignant pleural mesothelioma
Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause M...
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| Erschienen: |
2021 |
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© The Author(s) 2021 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 14(2021), 2 vom: 13. Dez. |
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| Übergeordnetes Werk: |
volume:14 ; year:2021 ; number:2 ; day:13 ; month:12 |
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| DOI / URN: |
10.15252/emmm.202013631 |
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SPR058032010 |
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| 520 | |a Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. | ||
| 520 | |a Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. | ||
| 520 | |a Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. | ||
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10.15252/emmm.202013631 doi (DE-627)SPR058032010 (SPR)emmm.202013631-e DE-627 ger DE-627 rakwb eng Marazioti, Antonia verfasserin aut KRAS signaling in malignant pleural mesothelioma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 Krontira, Anthi C verfasserin aut Behrend, Sabine J verfasserin (orcid)0000-0001-7549-1332 aut Giotopoulou, Georgia A verfasserin (orcid)0000-0001-5621-6802 aut Ntaliarda, Giannoula verfasserin (orcid)0000-0002-2299-6027 aut Blanquart, Christophe verfasserin aut Bayram, Hasan verfasserin (orcid)0000-0002-5236-766X aut Iliopoulou, Marianthi verfasserin aut Vreka, Malamati verfasserin aut Trassl, Lilith verfasserin aut Pepe, Mario A A verfasserin aut Hackl, Caroline M verfasserin aut Klotz, Laura V verfasserin aut Weiss, Stefanie A I verfasserin (orcid)0000-0002-4059-7417 aut Koch, Ina verfasserin aut Lindner, Michael verfasserin aut Hatz, Rudolph A verfasserin aut Behr, Juergen verfasserin aut Wagner, Darcy E verfasserin (orcid)0000-0003-3794-1309 aut Papadaki, Helen verfasserin aut Antimisiaris, Sophia G verfasserin aut Jean, Didier verfasserin (orcid)0000-0001-5823-7404 aut Deshayes, Sophie verfasserin aut Grégoire, Marc verfasserin aut Kayalar, Özgecan verfasserin (orcid)0000-0001-9107-2381 aut Mortazavi, Deniz verfasserin aut Dilege, Şükrü verfasserin aut Tanju, Serhan verfasserin (orcid)0000-0002-2363-233X aut Erus, Suat verfasserin (orcid)0000-0002-6162-3266 aut Yavuz, Ömer verfasserin (orcid)0000-0002-7366-2772 aut Bulutay, Pınar verfasserin aut Fırat, Pınar verfasserin aut Psallidas, Ioannis verfasserin aut Spella, Magda verfasserin (orcid)0000-0003-2505-7778 aut Giopanou, Ioanna verfasserin aut Lilis, Ioannis verfasserin (orcid)0000-0002-0483-4120 aut Lamort, Anne‐Sophie verfasserin (orcid)0000-0001-5495-9995 aut Stathopoulos, Georgios T verfasserin (orcid)0000-0002-9215-6461 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 2 vom: 13. Dez. 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| spelling |
10.15252/emmm.202013631 doi (DE-627)SPR058032010 (SPR)emmm.202013631-e DE-627 ger DE-627 rakwb eng Marazioti, Antonia verfasserin aut KRAS signaling in malignant pleural mesothelioma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 Krontira, Anthi C verfasserin aut Behrend, Sabine J verfasserin (orcid)0000-0001-7549-1332 aut Giotopoulou, Georgia A verfasserin (orcid)0000-0001-5621-6802 aut Ntaliarda, Giannoula verfasserin (orcid)0000-0002-2299-6027 aut Blanquart, Christophe verfasserin aut Bayram, Hasan verfasserin (orcid)0000-0002-5236-766X aut Iliopoulou, Marianthi verfasserin aut Vreka, Malamati verfasserin aut Trassl, Lilith verfasserin aut Pepe, Mario A A verfasserin aut Hackl, Caroline M verfasserin aut Klotz, Laura V verfasserin aut Weiss, Stefanie A I verfasserin (orcid)0000-0002-4059-7417 aut Koch, Ina verfasserin aut Lindner, Michael verfasserin aut Hatz, Rudolph A verfasserin aut Behr, Juergen verfasserin aut Wagner, Darcy E verfasserin (orcid)0000-0003-3794-1309 aut Papadaki, Helen verfasserin aut Antimisiaris, Sophia G verfasserin aut Jean, Didier verfasserin (orcid)0000-0001-5823-7404 aut Deshayes, Sophie verfasserin aut Grégoire, Marc verfasserin aut Kayalar, Özgecan verfasserin (orcid)0000-0001-9107-2381 aut Mortazavi, Deniz verfasserin aut Dilege, Şükrü verfasserin aut Tanju, Serhan verfasserin (orcid)0000-0002-2363-233X aut Erus, Suat verfasserin (orcid)0000-0002-6162-3266 aut Yavuz, Ömer verfasserin (orcid)0000-0002-7366-2772 aut Bulutay, Pınar verfasserin aut Fırat, Pınar verfasserin aut Psallidas, Ioannis verfasserin aut Spella, Magda verfasserin (orcid)0000-0003-2505-7778 aut Giopanou, Ioanna verfasserin aut Lilis, Ioannis verfasserin (orcid)0000-0002-0483-4120 aut Lamort, Anne‐Sophie verfasserin (orcid)0000-0001-5495-9995 aut Stathopoulos, Georgios T verfasserin (orcid)0000-0002-9215-6461 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 2 vom: 13. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:2 day:13 month:12 https://dx.doi.org/10.15252/emmm.202013631 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_2522 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_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 14 2021 2 13 12 |
| allfields_unstemmed |
10.15252/emmm.202013631 doi (DE-627)SPR058032010 (SPR)emmm.202013631-e DE-627 ger DE-627 rakwb eng Marazioti, Antonia verfasserin aut KRAS signaling in malignant pleural mesothelioma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 Krontira, Anthi C verfasserin aut Behrend, Sabine J verfasserin (orcid)0000-0001-7549-1332 aut Giotopoulou, Georgia A verfasserin (orcid)0000-0001-5621-6802 aut Ntaliarda, Giannoula verfasserin (orcid)0000-0002-2299-6027 aut Blanquart, Christophe verfasserin aut Bayram, Hasan verfasserin (orcid)0000-0002-5236-766X aut Iliopoulou, Marianthi verfasserin aut Vreka, Malamati verfasserin aut Trassl, Lilith verfasserin aut Pepe, Mario A A verfasserin aut Hackl, Caroline M verfasserin aut Klotz, Laura V verfasserin aut Weiss, Stefanie A I verfasserin (orcid)0000-0002-4059-7417 aut Koch, Ina verfasserin aut Lindner, Michael verfasserin aut Hatz, Rudolph A verfasserin aut Behr, Juergen verfasserin aut Wagner, Darcy E verfasserin (orcid)0000-0003-3794-1309 aut Papadaki, Helen verfasserin aut Antimisiaris, Sophia G verfasserin aut Jean, Didier verfasserin (orcid)0000-0001-5823-7404 aut Deshayes, Sophie verfasserin aut Grégoire, Marc verfasserin aut Kayalar, Özgecan verfasserin (orcid)0000-0001-9107-2381 aut Mortazavi, Deniz verfasserin aut Dilege, Şükrü verfasserin aut Tanju, Serhan verfasserin (orcid)0000-0002-2363-233X aut Erus, Suat verfasserin (orcid)0000-0002-6162-3266 aut Yavuz, Ömer verfasserin (orcid)0000-0002-7366-2772 aut Bulutay, Pınar verfasserin aut Fırat, Pınar verfasserin aut Psallidas, Ioannis verfasserin aut Spella, Magda verfasserin (orcid)0000-0003-2505-7778 aut Giopanou, Ioanna verfasserin aut Lilis, Ioannis verfasserin (orcid)0000-0002-0483-4120 aut Lamort, Anne‐Sophie verfasserin (orcid)0000-0001-5495-9995 aut Stathopoulos, Georgios T verfasserin (orcid)0000-0002-9215-6461 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 2 vom: 13. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:2 day:13 month:12 https://dx.doi.org/10.15252/emmm.202013631 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_2522 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_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 14 2021 2 13 12 |
| allfieldsGer |
10.15252/emmm.202013631 doi (DE-627)SPR058032010 (SPR)emmm.202013631-e DE-627 ger DE-627 rakwb eng Marazioti, Antonia verfasserin aut KRAS signaling in malignant pleural mesothelioma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 Krontira, Anthi C verfasserin aut Behrend, Sabine J verfasserin (orcid)0000-0001-7549-1332 aut Giotopoulou, Georgia A verfasserin (orcid)0000-0001-5621-6802 aut Ntaliarda, Giannoula verfasserin (orcid)0000-0002-2299-6027 aut Blanquart, Christophe verfasserin aut Bayram, Hasan verfasserin (orcid)0000-0002-5236-766X aut Iliopoulou, Marianthi verfasserin aut Vreka, Malamati verfasserin aut Trassl, Lilith verfasserin aut Pepe, Mario A A verfasserin aut Hackl, Caroline M verfasserin aut Klotz, Laura V verfasserin aut Weiss, Stefanie A I verfasserin (orcid)0000-0002-4059-7417 aut Koch, Ina verfasserin aut Lindner, Michael verfasserin aut Hatz, Rudolph A verfasserin aut Behr, Juergen verfasserin aut Wagner, Darcy E verfasserin (orcid)0000-0003-3794-1309 aut Papadaki, Helen verfasserin aut Antimisiaris, Sophia G verfasserin aut Jean, Didier verfasserin (orcid)0000-0001-5823-7404 aut Deshayes, Sophie verfasserin aut Grégoire, Marc verfasserin aut Kayalar, Özgecan verfasserin (orcid)0000-0001-9107-2381 aut Mortazavi, Deniz verfasserin aut Dilege, Şükrü verfasserin aut Tanju, Serhan verfasserin (orcid)0000-0002-2363-233X aut Erus, Suat verfasserin (orcid)0000-0002-6162-3266 aut Yavuz, Ömer verfasserin (orcid)0000-0002-7366-2772 aut Bulutay, Pınar verfasserin aut Fırat, Pınar verfasserin aut Psallidas, Ioannis verfasserin aut Spella, Magda verfasserin (orcid)0000-0003-2505-7778 aut Giopanou, Ioanna verfasserin aut Lilis, Ioannis verfasserin (orcid)0000-0002-0483-4120 aut Lamort, Anne‐Sophie verfasserin (orcid)0000-0001-5495-9995 aut Stathopoulos, Georgios T verfasserin (orcid)0000-0002-9215-6461 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 2 vom: 13. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:2 day:13 month:12 https://dx.doi.org/10.15252/emmm.202013631 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_2522 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_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 14 2021 2 13 12 |
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10.15252/emmm.202013631 doi (DE-627)SPR058032010 (SPR)emmm.202013631-e DE-627 ger DE-627 rakwb eng Marazioti, Antonia verfasserin aut KRAS signaling in malignant pleural mesothelioma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 Krontira, Anthi C verfasserin aut Behrend, Sabine J verfasserin (orcid)0000-0001-7549-1332 aut Giotopoulou, Georgia A verfasserin (orcid)0000-0001-5621-6802 aut Ntaliarda, Giannoula verfasserin (orcid)0000-0002-2299-6027 aut Blanquart, Christophe verfasserin aut Bayram, Hasan verfasserin (orcid)0000-0002-5236-766X aut Iliopoulou, Marianthi verfasserin aut Vreka, Malamati verfasserin aut Trassl, Lilith verfasserin aut Pepe, Mario A A verfasserin aut Hackl, Caroline M verfasserin aut Klotz, Laura V verfasserin aut Weiss, Stefanie A I verfasserin (orcid)0000-0002-4059-7417 aut Koch, Ina verfasserin aut Lindner, Michael verfasserin aut Hatz, Rudolph A verfasserin aut Behr, Juergen verfasserin aut Wagner, Darcy E verfasserin (orcid)0000-0003-3794-1309 aut Papadaki, Helen verfasserin aut Antimisiaris, Sophia G verfasserin aut Jean, Didier verfasserin (orcid)0000-0001-5823-7404 aut Deshayes, Sophie verfasserin aut Grégoire, Marc verfasserin aut Kayalar, Özgecan verfasserin (orcid)0000-0001-9107-2381 aut Mortazavi, Deniz verfasserin aut Dilege, Şükrü verfasserin aut Tanju, Serhan verfasserin (orcid)0000-0002-2363-233X aut Erus, Suat verfasserin (orcid)0000-0002-6162-3266 aut Yavuz, Ömer verfasserin (orcid)0000-0002-7366-2772 aut Bulutay, Pınar verfasserin aut Fırat, Pınar verfasserin aut Psallidas, Ioannis verfasserin aut Spella, Magda verfasserin (orcid)0000-0003-2505-7778 aut Giopanou, Ioanna verfasserin aut Lilis, Ioannis verfasserin (orcid)0000-0002-0483-4120 aut Lamort, Anne‐Sophie verfasserin (orcid)0000-0001-5495-9995 aut Stathopoulos, Georgios T verfasserin (orcid)0000-0002-9215-6461 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 2 vom: 13. Dez. 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English |
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Enthalten in EMBO Molecular Medicine 14(2021), 2 vom: 13. Dez. volume:14 year:2021 number:2 day:13 month:12 |
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Enthalten in EMBO Molecular Medicine 14(2021), 2 vom: 13. Dez. volume:14 year:2021 number:2 day:13 month:12 |
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EMBO Molecular Medicine |
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Marazioti, Antonia @@aut@@ Krontira, Anthi C @@aut@@ Behrend, Sabine J @@aut@@ Giotopoulou, Georgia A @@aut@@ Ntaliarda, Giannoula @@aut@@ Blanquart, Christophe @@aut@@ Bayram, Hasan @@aut@@ Iliopoulou, Marianthi @@aut@@ Vreka, Malamati @@aut@@ Trassl, Lilith @@aut@@ Pepe, Mario A A @@aut@@ Hackl, Caroline M @@aut@@ Klotz, Laura V @@aut@@ Weiss, Stefanie A I @@aut@@ Koch, Ina @@aut@@ Lindner, Michael @@aut@@ Hatz, Rudolph A @@aut@@ Behr, Juergen @@aut@@ Wagner, Darcy E @@aut@@ Papadaki, Helen @@aut@@ Antimisiaris, Sophia G @@aut@@ Jean, Didier @@aut@@ Deshayes, Sophie @@aut@@ Grégoire, Marc @@aut@@ Kayalar, Özgecan @@aut@@ Mortazavi, Deniz @@aut@@ Dilege, Şükrü @@aut@@ Tanju, Serhan @@aut@@ Erus, Suat @@aut@@ Yavuz, Ömer @@aut@@ Bulutay, Pınar @@aut@@ Fırat, Pınar @@aut@@ Psallidas, Ioannis @@aut@@ Spella, Magda @@aut@@ Giopanou, Ioanna @@aut@@ Lilis, Ioannis @@aut@@ Lamort, Anne‐Sophie @@aut@@ Stathopoulos, Georgios T @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058032010</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065237.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2021 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202013631</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058032010</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202013631-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">Marazioti, Antonia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">KRAS signaling in malignant pleural mesothelioma</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</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) 2021</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">asbestos</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BAP1</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">KRAS</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">NF2</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TP53</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Krontira, Anthi C</subfield><subfield code="e">verfasserin</subfield><subfield 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Marazioti, Antonia |
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KRAS signaling in malignant pleural mesothelioma asbestos (dpeaa)DE-He213 BAP1 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 NF2 (dpeaa)DE-He213 TP53 (dpeaa)DE-He213 |
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KRAS signaling in malignant pleural mesothelioma |
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KRAS signaling in malignant pleural mesothelioma |
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Marazioti, Antonia Krontira, Anthi C Behrend, Sabine J Giotopoulou, Georgia A Ntaliarda, Giannoula Blanquart, Christophe Bayram, Hasan Iliopoulou, Marianthi Vreka, Malamati Trassl, Lilith Pepe, Mario A A Hackl, Caroline M Klotz, Laura V Weiss, Stefanie A I Koch, Ina Lindner, Michael Hatz, Rudolph A Behr, Juergen Wagner, Darcy E Papadaki, Helen Antimisiaris, Sophia G Jean, Didier Deshayes, Sophie Grégoire, Marc Kayalar, Özgecan Mortazavi, Deniz Dilege, Şükrü Tanju, Serhan Erus, Suat Yavuz, Ömer Bulutay, Pınar Fırat, Pınar Psallidas, Ioannis Spella, Magda Giopanou, Ioanna Lilis, Ioannis Lamort, Anne‐Sophie Stathopoulos, Georgios T |
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Marazioti, Antonia |
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10.15252/emmm.202013631 |
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kras signaling in malignant pleural mesothelioma |
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KRAS signaling in malignant pleural mesothelioma |
| abstract |
Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. © The Author(s) 2021 |
| abstractGer |
Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. © The Author(s) 2021 |
| abstract_unstemmed |
Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset.KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines.Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance.Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome.Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. © The Author(s) 2021 |
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KRAS signaling in malignant pleural mesothelioma |
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Krontira, Anthi C Behrend, Sabine J Giotopoulou, Georgia A Ntaliarda, Giannoula Blanquart, Christophe Bayram, Hasan Iliopoulou, Marianthi Vreka, Malamati Trassl, Lilith Pepe, Mario A A Hackl, Caroline M Klotz, Laura V Weiss, Stefanie A I Koch, Ina Lindner, Michael Hatz, Rudolph A Behr, Juergen Wagner, Darcy E Papadaki, Helen Antimisiaris, Sophia G Jean, Didier Deshayes, Sophie Grégoire, Marc Kayalar, Özgecan Mortazavi, Deniz Dilege, Şükrü Tanju, Serhan Erus, Suat Yavuz, Ömer Bulutay, Pınar Fırat, Pınar Psallidas, Ioannis Spella, Magda Giopanou, Ioanna Lilis, Ioannis Lamort, Anne‐Sophie Stathopoulos, Georgios T |
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Krontira, Anthi C Behrend, Sabine J Giotopoulou, Georgia A Ntaliarda, Giannoula Blanquart, Christophe Bayram, Hasan Iliopoulou, Marianthi Vreka, Malamati Trassl, Lilith Pepe, Mario A A Hackl, Caroline M Klotz, Laura V Weiss, Stefanie A I Koch, Ina Lindner, Michael Hatz, Rudolph A Behr, Juergen Wagner, Darcy E Papadaki, Helen Antimisiaris, Sophia G Jean, Didier Deshayes, Sophie Grégoire, Marc Kayalar, Özgecan Mortazavi, Deniz Dilege, Şükrü Tanju, Serhan Erus, Suat Yavuz, Ömer Bulutay, Pınar Fırat, Pınar Psallidas, Ioannis Spella, Magda Giopanou, Ioanna Lilis, Ioannis Lamort, Anne‐Sophie Stathopoulos, Georgios T |
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|
| score |
7.400568 |