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Updated: Mar 21, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma
Virag Gehl1, Colm J O'Rourke1, Martin Cornillet2
1Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Background:
High serum levels of interleukin 6 (IL-6) predict poor prognosis in intrahepatic cholangiocarcinoma (iCCA), a malignancy that often develops in a chronically inflamed milieu. Here, tumour cells are capable of autonomously producing and engaging autocrine IL-6 signalling, yet the consequences of this remain unknown.
Objective:
This study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.
Design:
We generated CRISPR-activated IL-6high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.
Results:
Chronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.
Conclusions:
These findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.
