Role of lipid rafts in the FGFR2c-mediated oncogenic signaling by involvement of TRPA1 channel in pancreatic ductal adenocarcinoma cells

The aberrant expression of the mesenchymal FGFR2c variant in pancreatic ductal adenocarcinoma (PDAC)-derived cells enhances EMT and tumorigenic features, with PKC epsilon-dependent signaling emerging as the main downstream pathway involved. Since lipid rafts are specialized microdomains functioning as signaling hubs and considering their relevance in the induction of EMT and cell invasion in cancer, their potential contribution in FGFR2c-mediated tumorigenesis cannot be excluded. In this study, we aimed to assess whether a possible link exists between lipid raft stability and the oncogenic activity of FGFR2c by analyzing the impact of raft perturbation on the establishment of the aberrant FGFR2c/PKC epsilon axis in PDAC cells. Immunofluorescence and biochemical analyses revealed that ligand-dependent activation of FGFR2c led to an increased localization of the receptor within lipid rafts. Moreover, disruption of lipid rafts by methyl beta-cyclodextrin (M beta CD) attenuated the FGFR2c downstream signaling, as well as the consequent enhancement of EMT and of MCL1/SRC-mediated cell invasion. In addition, co-immunoprecipitation experiments, coupled to gene silencing approaches, highlighted the cation channel TRPA1 as a potential contributor to FGFR2c oncogenic signaling by regulating its recruitment to cholesterol-enriched signaling platforms. Overall, our findings indicate that FGFR2c, TRPA1 and lipid raft components represent promising targets for the development of novel cancer type-specific therapeutic strategies.