Loss of FGFR4 promotes the malignant phenotype of PDAC

D'Agosto, S. et al. (2022) Loss of FGFR4 promotes the malignant phenotype of PDAC. Oncogene, 41(38), pp. 4371-4384. (doi: 10.1038/s41388-022-02432-5) (PMID:35963908) (PMCID:PMC9481460)

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Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter
Authors: D'Agosto, S., Pezzini, F., Veghini, L., Delfino, P., Fiorini, C., Temgue Tane, G. D., Del Curatolo, A., Vicentini, C., Ferrari, G., Pasini, D., Andreani, S., Lupo, F., Fiorini, E., Lorenzon, G., Lawlor, R. T., Rusev, B., Malinova, A., Luchini, C., Milella, M., Sereni, E., Pea, A., Bassi, C., Bailey, P., Scarpa, A., Bria, E., and Corbo, V.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Oncogene
Publisher:Springer Nature
ISSN (Online):1476-5594
Published Online:13 August 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Oncogene 41(38): 4371-4384
Publisher Policy:Reproduced under a Creative Commons License

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