Impact of fibroblastic FGFBP2 mutation on pancreatic carcinogenesis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive with poor prognosis. Cancer-associated fibroblasts (CAFs) strongly influence tumor development. A somatic CAF mutation identified by our group is a guanine (G) to cytidine (C) change in Fibroblast Growth Factor Binding Protein 2 (FGFBP2) causing a threonine-to-serine substitution. This thesis investigates how this mutation affects fibroblasts and impacts PDAC progression. The FGFBP2 mutation increased fibroblast activation, proliferation, and migration. Conditioned medium (CM) derived from mutant fibroblasts enhanced PANC-1 cell growth and increased ERK1/2 phosphorylation. RNA-Seq of PANC-1 cells treated with mutant CM revealed upregulation of EHF. Single-cell RNA sequencing (scRNA-seq) showed EHF is mainly expressed in tumor cells and interacts with CAFs through PDGF signaling. In conclusion, the FGFBP2 mutation promotes fibroblast activation and supports tumor progression through ERK1/2 activation.