New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming

Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Colyn, Leticia [verfasserIn] Alvarez-Sola, Gloria Latasa, M. Ujue Uriarte, Iker Herranz, Jose M. Arechederra, Maria Vlachogiannis, George Rae, Colin Pineda-Lucena, Antonio Casadei-Gardini, Andrea Pedica, Federica Aldrighetti, Luca López-López, Angeles López-Gonzálvez, Angeles Barbas, Coral Ciordia, Sergio Van Liempd, Sebastiaan M. Falcón-Pérez, Juan M. Urman, Jesus Sangro, Bruno Vicent, Silve Iraburu, Maria J. Prosper, Felipe Nelson, Leonard J. Banales, Jesus M. Martinez-Chantar, Maria Luz Marin, Jose J. G. Braconi, Chiara Trautwein, Christian Corrales, Fernando J. Cubero, F. Javier Berasain, Carmen Fernandez-Barrena, Maite G. Avila, Matias A.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Cholangiocarcinoma Bile Inflammation Interleukin-6 KRAS G9a histone methyl-transferase Serine-glycine pathway Metabolic reprogramming

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: Journal of experimental & clinical cancer research - Berlin : Springer, 2008, 41(2022), 1 vom: 26. Mai
Übergeordnetes Werk:	volume:41 ; year:2022 ; number:1 ; day:26 ; month:05

Links:	Volltext

DOI / URN:	10.1186/s13046-022-02386-2

Katalog-ID:	SPR050740725

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245	1	0	\|a New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
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520			\|a Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.
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700	1		\|a Latasa, M. Ujue \|4 aut
700	1		\|a Uriarte, Iker \|4 aut
700	1		\|a Herranz, Jose M. \|4 aut
700	1		\|a Arechederra, Maria \|4 aut
700	1		\|a Vlachogiannis, George \|4 aut
700	1		\|a Rae, Colin \|4 aut
700	1		\|a Pineda-Lucena, Antonio \|4 aut
700	1		\|a Casadei-Gardini, Andrea \|4 aut
700	1		\|a Pedica, Federica \|4 aut
700	1		\|a Aldrighetti, Luca \|4 aut
700	1		\|a López-López, Angeles \|4 aut
700	1		\|a López-Gonzálvez, Angeles \|4 aut
700	1		\|a Barbas, Coral \|4 aut
700	1		\|a Ciordia, Sergio \|4 aut
700	1		\|a Van Liempd, Sebastiaan M. \|4 aut
700	1		\|a Falcón-Pérez, Juan M. \|4 aut
700	1		\|a Urman, Jesus \|4 aut
700	1		\|a Sangro, Bruno \|4 aut
700	1		\|a Vicent, Silve \|4 aut
700	1		\|a Iraburu, Maria J. \|4 aut
700	1		\|a Prosper, Felipe \|4 aut
700	1		\|a Nelson, Leonard J. \|4 aut
700	1		\|a Banales, Jesus M. \|4 aut
700	1		\|a Martinez-Chantar, Maria Luz \|4 aut
700	1		\|a Marin, Jose J. G. \|4 aut
700	1		\|a Braconi, Chiara \|4 aut
700	1		\|a Trautwein, Christian \|4 aut
700	1		\|a Corrales, Fernando J. \|4 aut
700	1		\|a Cubero, F. Javier \|4 aut
700	1		\|a Berasain, Carmen \|4 aut
700	1		\|a Fernandez-Barrena, Maite G. \|4 aut
700	1		\|a Avila, Matias A. \|0 (orcid)0000-0001-6570-3557 \|4 aut
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allfields	10.1186/s13046-022-02386-2 doi (DE-627)SPR050740725 (SPR)s13046-022-02386-2-e DE-627 ger DE-627 rakwb eng Colyn, Leticia verfasserin aut New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213 Alvarez-Sola, Gloria aut Latasa, M. Ujue aut Uriarte, Iker aut Herranz, Jose M. aut Arechederra, Maria aut Vlachogiannis, George aut Rae, Colin aut Pineda-Lucena, Antonio aut Casadei-Gardini, Andrea aut Pedica, Federica aut Aldrighetti, Luca aut López-López, Angeles aut López-Gonzálvez, Angeles aut Barbas, Coral aut Ciordia, Sergio aut Van Liempd, Sebastiaan M. aut Falcón-Pérez, Juan M. aut Urman, Jesus aut Sangro, Bruno aut Vicent, Silve aut Iraburu, Maria J. aut Prosper, Felipe aut Nelson, Leonard J. aut Banales, Jesus M. aut Martinez-Chantar, Maria Luz aut Marin, Jose J. G. aut Braconi, Chiara aut Trautwein, Christian aut Corrales, Fernando J. aut Cubero, F. Javier aut Berasain, Carmen aut Fernandez-Barrena, Maite G. aut Avila, Matias A. (orcid)0000-0001-6570-3557 aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 41(2022), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:41 year:2022 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-022-02386-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 41 2022 1 26 05
spelling	10.1186/s13046-022-02386-2 doi (DE-627)SPR050740725 (SPR)s13046-022-02386-2-e DE-627 ger DE-627 rakwb eng Colyn, Leticia verfasserin aut New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213 Alvarez-Sola, Gloria aut Latasa, M. Ujue aut Uriarte, Iker aut Herranz, Jose M. aut Arechederra, Maria aut Vlachogiannis, George aut Rae, Colin aut Pineda-Lucena, Antonio aut Casadei-Gardini, Andrea aut Pedica, Federica aut Aldrighetti, Luca aut López-López, Angeles aut López-Gonzálvez, Angeles aut Barbas, Coral aut Ciordia, Sergio aut Van Liempd, Sebastiaan M. aut Falcón-Pérez, Juan M. aut Urman, Jesus aut Sangro, Bruno aut Vicent, Silve aut Iraburu, Maria J. aut Prosper, Felipe aut Nelson, Leonard J. aut Banales, Jesus M. aut Martinez-Chantar, Maria Luz aut Marin, Jose J. G. aut Braconi, Chiara aut Trautwein, Christian aut Corrales, Fernando J. aut Cubero, F. Javier aut Berasain, Carmen aut Fernandez-Barrena, Maite G. aut Avila, Matias A. (orcid)0000-0001-6570-3557 aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 41(2022), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:41 year:2022 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-022-02386-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 41 2022 1 26 05
allfields_unstemmed	10.1186/s13046-022-02386-2 doi (DE-627)SPR050740725 (SPR)s13046-022-02386-2-e DE-627 ger DE-627 rakwb eng Colyn, Leticia verfasserin aut New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213 Alvarez-Sola, Gloria aut Latasa, M. Ujue aut Uriarte, Iker aut Herranz, Jose M. aut Arechederra, Maria aut Vlachogiannis, George aut Rae, Colin aut Pineda-Lucena, Antonio aut Casadei-Gardini, Andrea aut Pedica, Federica aut Aldrighetti, Luca aut López-López, Angeles aut López-Gonzálvez, Angeles aut Barbas, Coral aut Ciordia, Sergio aut Van Liempd, Sebastiaan M. aut Falcón-Pérez, Juan M. aut Urman, Jesus aut Sangro, Bruno aut Vicent, Silve aut Iraburu, Maria J. aut Prosper, Felipe aut Nelson, Leonard J. aut Banales, Jesus M. aut Martinez-Chantar, Maria Luz aut Marin, Jose J. G. aut Braconi, Chiara aut Trautwein, Christian aut Corrales, Fernando J. aut Cubero, F. Javier aut Berasain, Carmen aut Fernandez-Barrena, Maite G. aut Avila, Matias A. (orcid)0000-0001-6570-3557 aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 41(2022), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:41 year:2022 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-022-02386-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 41 2022 1 26 05
allfieldsGer	10.1186/s13046-022-02386-2 doi (DE-627)SPR050740725 (SPR)s13046-022-02386-2-e DE-627 ger DE-627 rakwb eng Colyn, Leticia verfasserin aut New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213 Alvarez-Sola, Gloria aut Latasa, M. Ujue aut Uriarte, Iker aut Herranz, Jose M. aut Arechederra, Maria aut Vlachogiannis, George aut Rae, Colin aut Pineda-Lucena, Antonio aut Casadei-Gardini, Andrea aut Pedica, Federica aut Aldrighetti, Luca aut López-López, Angeles aut López-Gonzálvez, Angeles aut Barbas, Coral aut Ciordia, Sergio aut Van Liempd, Sebastiaan M. aut Falcón-Pérez, Juan M. aut Urman, Jesus aut Sangro, Bruno aut Vicent, Silve aut Iraburu, Maria J. aut Prosper, Felipe aut Nelson, Leonard J. aut Banales, Jesus M. aut Martinez-Chantar, Maria Luz aut Marin, Jose J. G. aut Braconi, Chiara aut Trautwein, Christian aut Corrales, Fernando J. aut Cubero, F. Javier aut Berasain, Carmen aut Fernandez-Barrena, Maite G. aut Avila, Matias A. (orcid)0000-0001-6570-3557 aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 41(2022), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:41 year:2022 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-022-02386-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 41 2022 1 26 05
allfieldsSound	10.1186/s13046-022-02386-2 doi (DE-627)SPR050740725 (SPR)s13046-022-02386-2-e DE-627 ger DE-627 rakwb eng Colyn, Leticia verfasserin aut New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213 Alvarez-Sola, Gloria aut Latasa, M. Ujue aut Uriarte, Iker aut Herranz, Jose M. aut Arechederra, Maria aut Vlachogiannis, George aut Rae, Colin aut Pineda-Lucena, Antonio aut Casadei-Gardini, Andrea aut Pedica, Federica aut Aldrighetti, Luca aut López-López, Angeles aut López-Gonzálvez, Angeles aut Barbas, Coral aut Ciordia, Sergio aut Van Liempd, Sebastiaan M. aut Falcón-Pérez, Juan M. aut Urman, Jesus aut Sangro, Bruno aut Vicent, Silve aut Iraburu, Maria J. aut Prosper, Felipe aut Nelson, Leonard J. aut Banales, Jesus M. aut Martinez-Chantar, Maria Luz aut Marin, Jose J. G. aut Braconi, Chiara aut Trautwein, Christian aut Corrales, Fernando J. aut Cubero, F. Javier aut Berasain, Carmen aut Fernandez-Barrena, Maite G. aut Avila, Matias A. (orcid)0000-0001-6570-3557 aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 41(2022), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:41 year:2022 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-022-02386-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 41 2022 1 26 05
language	English
source	Enthalten in Journal of experimental & clinical cancer research 41(2022), 1 vom: 26. Mai volume:41 year:2022 number:1 day:26 month:05
sourceStr	Enthalten in Journal of experimental & clinical cancer research 41(2022), 1 vom: 26. Mai volume:41 year:2022 number:1 day:26 month:05
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Cholangiocarcinoma Bile Inflammation Interleukin-6 KRAS G9a histone methyl-transferase Serine-glycine pathway Metabolic reprogramming
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container_title	Journal of experimental & clinical cancer research
authorswithroles_txt_mv	Colyn, Leticia @@aut@@ Alvarez-Sola, Gloria @@aut@@ Latasa, M. Ujue @@aut@@ Uriarte, Iker @@aut@@ Herranz, Jose M. @@aut@@ Arechederra, Maria @@aut@@ Vlachogiannis, George @@aut@@ Rae, Colin @@aut@@ Pineda-Lucena, Antonio @@aut@@ Casadei-Gardini, Andrea @@aut@@ Pedica, Federica @@aut@@ Aldrighetti, Luca @@aut@@ López-López, Angeles @@aut@@ López-Gonzálvez, Angeles @@aut@@ Barbas, Coral @@aut@@ Ciordia, Sergio @@aut@@ Van Liempd, Sebastiaan M. @@aut@@ Falcón-Pérez, Juan M. @@aut@@ Urman, Jesus @@aut@@ Sangro, Bruno @@aut@@ Vicent, Silve @@aut@@ Iraburu, Maria J. @@aut@@ Prosper, Felipe @@aut@@ Nelson, Leonard J. @@aut@@ Banales, Jesus M. @@aut@@ Martinez-Chantar, Maria Luz @@aut@@ Marin, Jose J. G. @@aut@@ Braconi, Chiara @@aut@@ Trautwein, Christian @@aut@@ Corrales, Fernando J. @@aut@@ Cubero, F. Javier @@aut@@ Berasain, Carmen @@aut@@ Fernandez-Barrena, Maite G. @@aut@@ Avila, Matias A. @@aut@@
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Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cholangiocarcinoma</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Bile</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Inflammation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Interleukin-6</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">G9a histone methyl-transferase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Serine-glycine pathway</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Metabolic reprogramming</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Alvarez-Sola, Gloria</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Latasa, M. 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author	Colyn, Leticia
spellingShingle	Colyn, Leticia misc Cholangiocarcinoma misc Bile misc Inflammation misc Interleukin-6 misc KRAS misc G9a histone methyl-transferase misc Serine-glycine pathway misc Metabolic reprogramming New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
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topic_title	New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming Cholangiocarcinoma (dpeaa)DE-He213 Bile (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 Interleukin-6 (dpeaa)DE-He213 KRAS (dpeaa)DE-He213 G9a histone methyl-transferase (dpeaa)DE-He213 Serine-glycine pathway (dpeaa)DE-He213 Metabolic reprogramming (dpeaa)DE-He213
topic	misc Cholangiocarcinoma misc Bile misc Inflammation misc Interleukin-6 misc KRAS misc G9a histone methyl-transferase misc Serine-glycine pathway misc Metabolic reprogramming
topic_unstemmed	misc Cholangiocarcinoma misc Bile misc Inflammation misc Interleukin-6 misc KRAS misc G9a histone methyl-transferase misc Serine-glycine pathway misc Metabolic reprogramming
topic_browse	misc Cholangiocarcinoma misc Bile misc Inflammation misc Interleukin-6 misc KRAS misc G9a histone methyl-transferase misc Serine-glycine pathway misc Metabolic reprogramming
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title	New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
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title_full	New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
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author_browse	Colyn, Leticia Alvarez-Sola, Gloria Latasa, M. Ujue Uriarte, Iker Herranz, Jose M. Arechederra, Maria Vlachogiannis, George Rae, Colin Pineda-Lucena, Antonio Casadei-Gardini, Andrea Pedica, Federica Aldrighetti, Luca López-López, Angeles López-Gonzálvez, Angeles Barbas, Coral Ciordia, Sergio Van Liempd, Sebastiaan M. Falcón-Pérez, Juan M. Urman, Jesus Sangro, Bruno Vicent, Silve Iraburu, Maria J. Prosper, Felipe Nelson, Leonard J. Banales, Jesus M. Martinez-Chantar, Maria Luz Marin, Jose J. G. Braconi, Chiara Trautwein, Christian Corrales, Fernando J. Cubero, F. Javier Berasain, Carmen Fernandez-Barrena, Maite G. Avila, Matias A.
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title_sort	new molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and kras co-opted epigenetic mediators driving metabolic reprogramming
title_auth	New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
abstract	Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. © The Author(s) 2022
abstractGer	Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. © The Author(s) 2022
abstract_unstemmed	Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA. © The Author(s) 2022
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title_short	New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming
url	https://dx.doi.org/10.1186/s13046-022-02386-2
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author2	Alvarez-Sola, Gloria Latasa, M. Ujue Uriarte, Iker Herranz, Jose M. Arechederra, Maria Vlachogiannis, George Rae, Colin Pineda-Lucena, Antonio Casadei-Gardini, Andrea Pedica, Federica Aldrighetti, Luca López-López, Angeles López-Gonzálvez, Angeles Barbas, Coral Ciordia, Sergio Van Liempd, Sebastiaan M. Falcón-Pérez, Juan M. Urman, Jesus Sangro, Bruno Vicent, Silve Iraburu, Maria J. Prosper, Felipe Nelson, Leonard J. Banales, Jesus M. Martinez-Chantar, Maria Luz Marin, Jose J. G. Braconi, Chiara Trautwein, Christian Corrales, Fernando J. Cubero, F. Javier Berasain, Carmen Fernandez-Barrena, Maite G. Avila, Matias A.
author2Str	Alvarez-Sola, Gloria Latasa, M. Ujue Uriarte, Iker Herranz, Jose M. Arechederra, Maria Vlachogiannis, George Rae, Colin Pineda-Lucena, Antonio Casadei-Gardini, Andrea Pedica, Federica Aldrighetti, Luca López-López, Angeles López-Gonzálvez, Angeles Barbas, Coral Ciordia, Sergio Van Liempd, Sebastiaan M. Falcón-Pérez, Juan M. Urman, Jesus Sangro, Bruno Vicent, Silve Iraburu, Maria J. Prosper, Felipe Nelson, Leonard J. Banales, Jesus M. Martinez-Chantar, Maria Luz Marin, Jose J. G. Braconi, Chiara Trautwein, Christian Corrales, Fernando J. Cubero, F. Javier Berasain, Carmen Fernandez-Barrena, Maite G. Avila, Matias A.
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doi_str	10.1186/s13046-022-02386-2
up_date	2024-07-03T17:29:07.893Z
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Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + $ CCl_{4} $ + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-$ KRAS^{G12D} $ cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant $ KRAS^{G12D} $ can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, $ KRAS^{G12D} $ promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. $ KRAS^{G12D} $ CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. 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New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming

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