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Role of lipid rafts in the FGFR2c-mediated oncogenic signaling by involvement of TRPA1 channel in pancreatic ductal adenocarcinoma cells
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  • Published: 24 February 2026

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

  • Vanessa Mancini  ORCID: orcid.org/0000-0001-5176-27241 na1,
  • Valeria Manganelli2 na1,
  • Tina Garofalo  ORCID: orcid.org/0000-0003-0645-25103,
  • Maurizio Sorice2,
  • Salvatore Raffa1,4,
  • Dafne Scullari1 na1,
  • Danilo Ranieri5 na1 &
  • …
  • Francesca Belleudi1 na1 

Cell Death & Disease , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer therapy
  • Growth factor signalling

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.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Material.

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Author notes

  1. These authors contributed equally: Vanessa Mancini, Valeria Manganelli, Dafne Scullari, Danilo Ranieri, Francesca Belleudi.

Authors and Affiliations

  1. Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Vanessa Mancini, Salvatore Raffa, Dafne Scullari & Francesca Belleudi

  2. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Valeria Manganelli & Maurizio Sorice

  3. Wellbeing, Health and Environmental Sustainability, Sapienza University of Rome, Rome, Italy

    Tina Garofalo

  4. Ultrastructural Pathology Lab., Medical Genetics and Advanced Cellular Diagnostics Unit, Sant’Andrea University Hospital, Rome, Italy

    Salvatore Raffa

  5. Department of Life Sciences, Health and Health Professions, Link Campus University, Rome, Italy

    Danilo Ranieri

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Contributions

Study design: FB and DR; experimental work and data analysis: VM, SR, V Mang, TG and DS. Manuscript writing: FB, VM, and DR. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Vanessa Mancini.

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The authors declare no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. Ethical approval and informed consent were not necessary. All experiments were performed exclusively using commercially available immortalized cell lines.

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Mancini, V., Manganelli, V., Garofalo, T. et al. Role of lipid rafts in the FGFR2c-mediated oncogenic signaling by involvement of TRPA1 channel in pancreatic ductal adenocarcinoma cells. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08513-7

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  • Received: 12 May 2025

  • Revised: 19 January 2026

  • Accepted: 16 February 2026

  • Published: 24 February 2026

  • DOI: https://doi.org/10.1038/s41419-026-08513-7

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