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

Colyn, L. et al. (2022) 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 and Clinical Cancer Research, 41, 183. (doi: 10.1186/s13046-022-02386-2)

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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 + 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Rae, Dr Colin and Braconi, Dr Chiara
Authors: Colyn, L., Alvarez-Sola, G., Latasa, M. U., Uriarte, I., Herranz, J. M., Arechederra, M., Vlachogiannis, G., Rae, C., Pineda-Lucena, A., Casadei-Gardini, A., Pedica, F., Aldrighetti, L., López-López, A., López-Gonzálvez, A., Barbas, C., Ciordia, S., Van Liempd, S. M., Falcón-Pérez, J. M., Urman, J., Sangro, B., Vicent, S., Iraburu, M. J., Prosper, F., Nelson, L. J., Banales, J. M., Martinez-Chantar, M. L., Marin, J. J. G., Braconi, C., Trautwein, C., Corrales, F. J., Cubero, F. J., Berasain, C., Fernandez-Barrena, M. G., and Avila, M. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Experimental and Clinical Cancer Research
Publisher:BioMed Central
ISSN (Online):1756-9966
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Experimental and Clinical Cancer Research 41: 183
Publisher Policy:Reproduced under a Creative Commons License

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