Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Chen, Chaobo; Wu, Hanghang; Ye, Hui; Tortajada, Agustín; Rodríguez‐Perales, Sandra; Torres-Ruíz, Raúl; Vidal, August; Peligros, María Isabel; Reißing, Johanna; Bruns, Tony; Mohamed, Mohamed Ramadan; Zheng, Kang; Lujambio, Amaia; Iraburu, María J.; Colyn, Leticia; Latasa, M Ujue; Arechederra, María; Fernández‐Barrena, Maite G.; Berasain, Carmen; Vaquero, Javier; Bañares, Rafael; Nelson, Leonard J.; Davis, Roger J.; Martı́nez-Naves, Eduardo; Nevzorova, Yulia A.; Villanueva, Alberto; Avila, Matı́as A.; Cubero, Francisco Javier

doi:10.3390/cancers14010078

Cited by 4 publications

(1 citation statement)

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“…We recently described and validated a model in which mice with hepatocellular c-Jun N-terminal kinase 1/2 ( Jnk1/2 ) deletion ( Jnk Δhepa ) treated with CCl 4 and DEN ( Jnk Δhepa + CCl 4 + DEN model) develop transplantable CCAs in a context of inflammation, fibrosis and robust MAPK activation in tumoral tissues [ 28 , 48 ] (Fig. 8 a).…”

Section: Resultsmentioning

confidence: 99%

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

Colyn

Álvarez‐Sola

Latasa

et al. 2022

J Exp Clin Cancer Res

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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.

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Section: Resultsmentioning

confidence: 99%

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

Colyn

Álvarez‐Sola

Latasa

et al. 2022

J Exp Clin Cancer Res

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A prognostic risk model, tumor immune environment modulation, and drug prediction of ferroptosis and amino acid metabolism-related genes in hepatocellular carcinoma

Zhang

Cao

et al. 2023

Human Cell

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Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

Elurbide,

Colyn,

Latasa

et al. 2024

Gut

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BackgroundCholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.ObjectiveWe characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA.DesignWe evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)—an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors—in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms.ResultsPRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions.ConclusionPRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

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Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Cited by 4 publications

References 44 publications

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

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

A prognostic risk model, tumor immune environment modulation, and drug prediction of ferroptosis and amino acid metabolism-related genes in hepatocellular carcinoma

Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

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