Loss of FGFR4 promotes the malignant phenotype of PDAC

Autor: Sabrina D’Agosto, Francesco Pezzini, Lisa Veghini, Pietro Delfino, Claudia Fiorini, Gael D. Temgue Tane, Anais Del Curatolo, Caterina Vicentini, Giorgia Ferrari, Davide Pasini, Silvia Andreani, Francesca Lupo, Elena Fiorini, Giulia Lorenzon, Rita T. Lawlor, Borislav Rusev, Antonia Malinova, Claudio Luchini, Michele Milella, Elisabetta Sereni, Antonio Pea, Claudio Bassi, Peter Bailey, Aldo Scarpa, Emilio Bria, Vincenzo Corbo
Rok vydání: 2022
Předmět:
Zdroj: Oncogene. 41:4371-4384
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-022-02432-5
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: