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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-022-02386-2 |
| _version_ | 1818207015015546880 |
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| author | Leticia Colyn Gloria Alvarez-Sola M. Ujue Latasa Iker Uriarte Jose M. Herranz Maria Arechederra George Vlachogiannis Colin Rae Antonio Pineda-Lucena Andrea Casadei-Gardini Federica Pedica Luca Aldrighetti Angeles López-López Angeles López-Gonzálvez Coral Barbas Sergio Ciordia Sebastiaan M. Van Liempd Juan M. Falcón-Pérez Jesus Urman Bruno Sangro Silve Vicent Maria J. Iraburu Felipe Prosper Leonard J. Nelson Jesus M. Banales Maria Luz Martinez-Chantar Jose J. G. Marin Chiara Braconi Christian Trautwein Fernando J. Corrales F. Javier Cubero Carmen Berasain Maite G. Fernandez-Barrena Matias A. Avila |
| author_facet | Leticia Colyn Gloria Alvarez-Sola M. Ujue Latasa Iker Uriarte Jose M. Herranz Maria Arechederra George Vlachogiannis Colin Rae Antonio Pineda-Lucena Andrea Casadei-Gardini Federica Pedica Luca Aldrighetti Angeles López-López Angeles López-Gonzálvez Coral Barbas Sergio Ciordia Sebastiaan M. Van Liempd Juan M. Falcón-Pérez Jesus Urman Bruno Sangro Silve Vicent Maria J. Iraburu Felipe Prosper Leonard J. Nelson Jesus M. Banales Maria Luz Martinez-Chantar Jose J. G. Marin Chiara Braconi Christian Trautwein Fernando J. Corrales F. Javier Cubero Carmen Berasain Maite G. Fernandez-Barrena Matias A. Avila |
| author_sort | Leticia Colyn |
| collection | DOAJ |
| description | 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 (Jnk Δhepa + CCl4 + 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-KRASG12D 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 KRASG12D 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, KRASG12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRASG12D 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. |
| first_indexed | 2024-12-12T04:22:12Z |
| format | Article |
| id | doaj.art-278c7dac66c24c988487ac905912005b |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-12T04:22:12Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-278c7dac66c24c988487ac905912005b2022-12-22T00:38:18ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-05-0141111810.1186/s13046-022-02386-2New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogrammingLeticia Colyn0Gloria Alvarez-Sola1M. Ujue Latasa2Iker Uriarte3Jose M. Herranz4Maria Arechederra5George Vlachogiannis6Colin Rae7Antonio Pineda-Lucena8Andrea Casadei-Gardini9Federica Pedica10Luca Aldrighetti11Angeles López-López12Angeles López-Gonzálvez13Coral Barbas14Sergio Ciordia15Sebastiaan M. Van Liempd16Juan M. Falcón-Pérez17Jesus Urman18Bruno Sangro19Silve Vicent20Maria J. Iraburu21Felipe Prosper22Leonard J. Nelson23Jesus M. Banales24Maria Luz Martinez-Chantar25Jose J. G. Marin26Chiara Braconi27Christian Trautwein28Fernando J. Corrales29F. Javier Cubero30Carmen Berasain31Maite G. Fernandez-Barrena32Matias A. Avila33Hepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraDivision of Surgery and Cancer, Imperial College LondonInstitute of Cancer Sciences, The University of GlasgowMolecular Therapies Program, CIMA, Universidad de NavarraDepartment of Oncology, San Raffaele HospitalDepartment of Experimental Oncology, Pathology Unit, IRCCS San Raffaele Scientific InstituteHepatobiliary Surgery Division, Vita-Salute San Raffaele University, IRCCS San Raffaele HospitalCentro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia University San Pablo CEUCentro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia University San Pablo CEUCentro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia University San Pablo CEUFunctional Proteomics Laboratory, CNB-CSIC, Proteored-ISCIIIExosomes Laboratory and Metabolomics Platform, CIC bioGUNE-BRTACIBERehdInstituto de Investigaciones Sanitarias de Navarra IdiSNACIBERehdInstituto de Investigaciones Sanitarias de Navarra IdiSNADepartment of Biochemistry and Genetics, University of NavarraOncohematology Program, CIMA, Universidad de NavarraInstitute of Engineering, School of Engineering, Faraday Building, The University of EdimburghCIBERehdCIBERehdCIBERehdInstitute of Cancer Sciences, The University of GlasgowDepartment of Internal Medicine III, University Hospital, RWTH AachenCIBERehdCIBERehdHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraHepatology Program, CIMA, Universidad de NavarraAbstract 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 (Jnk Δhepa + CCl4 + 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-KRASG12D 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 KRASG12D 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, KRASG12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRASG12D 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.https://doi.org/10.1186/s13046-022-02386-2CholangiocarcinomaBileInflammationInterleukin-6KRASG9a histone methyl-transferase |
| spellingShingle | Leticia Colyn Gloria Alvarez-Sola M. Ujue Latasa Iker Uriarte Jose M. Herranz Maria Arechederra George Vlachogiannis Colin Rae Antonio Pineda-Lucena Andrea Casadei-Gardini Federica Pedica Luca Aldrighetti Angeles López-López Angeles López-Gonzálvez Coral Barbas Sergio Ciordia Sebastiaan M. Van Liempd Juan M. Falcón-Pérez Jesus Urman Bruno Sangro Silve Vicent Maria J. Iraburu Felipe Prosper Leonard J. Nelson Jesus M. Banales Maria Luz Martinez-Chantar Jose J. G. Marin Chiara Braconi Christian Trautwein Fernando J. Corrales F. Javier Cubero Carmen Berasain Maite G. Fernandez-Barrena Matias A. Avila New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming Journal of Experimental & Clinical Cancer Research Cholangiocarcinoma Bile Inflammation Interleukin-6 KRAS G9a histone methyl-transferase |
| title | New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming |
| title_full | New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming |
| title_fullStr | New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming |
| title_full_unstemmed | New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming |
| title_short | New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming |
| title_sort | new molecular mechanisms in cholangiocarcinoma signals triggering interleukin 6 production in tumor cells and kras co opted epigenetic mediators driving metabolic reprogramming |
| topic | Cholangiocarcinoma Bile Inflammation Interleukin-6 KRAS G9a histone methyl-transferase |
| url | https://doi.org/10.1186/s13046-022-02386-2 |
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