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

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 TGFß signaling, but the molecular drivers of metastasis remain unclear. Here, we show that TGFß 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 human CRC patients in vivo. Combined, our data reveal that TGFß-driven CAF signaling actively contributes to the formation of a neutrophil-dependent, pre-metastatic hepatic niche in the metastatic phenotype of CMS4 CRC. Overall design: Bulk RNA seq of murine wild type colon tissue, organoid lines and colonic tumors from intracolonic transplants of these lines.