TGFβ signaling in cancer-associated fibroblasts drives a hepatic gp130-dependent pro-metastatic inflammatory program in colorectal cancer

Author(s):
Harryvan, T.J.; Abudukelimu, S. (0000-0002-3093-3261); Stouten, I. (0009-0002-8136-4262); Wel, E.J. van der; Janson, S.G.T.; Lenos, K.J.; Lannagan, T.R.M.; White, M.; Sansom, O.J.; Verdegaal, E.M.E. (0000-0002-4449-8707); Hawinkels, L.J.A.C. (0000-0002-2274-9325)
Published
2025
Publication type
Article / Letter to editor

Abstract

The Consensus Molecular Subtype 4 (CMS4) of colorectal cancer (CRC) has the worst prognosis and the highest frequency of hepatic metastases. It is characterized by abundant cancer-associated fibroblasts (CAFs) in the tumor microenvironment and active TGF beta signaling, but the molecular drivers of metastasis remain unclear. Here, we show that TGF beta signaling in CRC patient-derived CAFs from the primary tumor induces production of IL-6 family cytokines, particularly IL-6 and IL-11. These cytokines stimulate hepatocytes to express myeloid chemoattractants, including SAA1, through gp130-dependent JAK/STAT signaling. This promotes neutrophil recruitment to the liver, potentially creating a pro-metastatic niche. This IL-6 family-JAK/ STAT stromal signaling axis is active in both a murine model of CMS4 as well as in patients with human CRC in vivo. Combined, our data reveal that TGF beta-driven CAF signaling actively contributes to the formation of a neutrophil-depen dent, pre-metastatic hepatic niche in the metastatic phenotype of CMS4 CRC.

Date issued
2025-11-21
Language
English
Publisher
CELL PRESS
Is part of
iScience (2025), No. 11
hdl
1887/4297775
doi
10.1016/j.isci.2025.113696