FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Abstract Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

(A) The expression of FGF19 was higher in CRC tissues than in normal tissues (GSE87211), higher in CRC tissues with liver metastasis (LM(+)) than in CRC tissues without liver metastasis (LM(-)), and higher in CRLM than in primary CRC tissues (GSE41568).
(B) Kaplan-Meier survival curves of overall survival for CRC patients with low (n=247) and high (n=161) FGF19 expression.Patients were stratified to FGF19-high or low groups by the cutoff value.

(D)
The correlation between FGF19 expression and liver metastasis was analyzed with Chi-square test.
(E) Receiver operator characteristic (ROC) curve to predict liver metastasis from FGF19 expression in CRC tumors.AUC: area under curve.

(G)
The correlation between serological FGF19 levels and liver metastasis was analyzed with Chi-square test.
In (C), data were subjected to paired Student's t-test.