FGFBP2 p.T186S mutation in tumor associated fibroblasts supports progression of pancreatic cancer through autocrine and paracrine mechanisms

Pancreatic cancer is one of the most aggressive human tumors with an extremely poor prognosis. FGFBP2 p.T186S mutation expressing cells (SV80m) displayed increased expression of activation markers and cytokines as compared to controls. SV80m cells exhibited increased proliferation and migration. Further, conditioned medium derived from SV80m promoted growth of the pancreatic cancer cell line PANC-1, and resulted in increased activation of the ERK1/2 signaling pathway. RNA sequencing (RNA-Seq) analysis of PANC-1 cells treated with conditioned media derived from SV80m revealed upregulation of the ETS homologous factor (EHF) gene. Single-cell RNA sequencing (scRNA-seq) analysis showed that EHF is primarily expressed in tumor cells and regulates fibroblasts through the platelet-derived growth factor (PDGF) signaling pathway. In addition, spatial transcriptomic analysis revealed a correlation between EHF expression and CAF markers ACTA2, POSTN, and COL1A1. In conclusion, our study shows that the FGFBP2 p.T186S point mutation promotes fibroblast activation which potentially influences tumor progression by inducing pancreatic cancer cell proliferation.