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

## TL;DR

This study explores how lipid rafts and the FGFR2c receptor contribute to cancer progression in pancreatic cells, suggesting new therapeutic targets.

## Contribution

The study identifies TRPA1 as a novel contributor to FGFR2c-mediated oncogenic signaling through lipid raft interactions in pancreatic cancer.

## Key findings

- FGFR2c activation increases its localization within lipid rafts in pancreatic cancer cells.
- Disruption of lipid rafts reduces FGFR2c downstream signaling and cancer-promoting effects.
- TRPA1 is shown to regulate FGFR2c recruitment to lipid rafts, contributing to oncogenic signaling.

## Abstract

The aberrant expression of the mesenchymal FGFR2c variant in pancreatic ductal adenocarcinoma (PDAC)-derived cells enhances EMT and tumorigenic features, with PKCε-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/PKCε 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 β-cyclodextrin (MβCD) 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.