Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer

Lisa Veghini, Davide Pasini, Rui Fang, Pietro Delfino, Dea Filippini, Christian Neander, Caterina Vicentini, Elena Fiorini, Francesca Lupo, Sabrina L. D’Agosto, Carmine Carbone, Antonio Agostini, Geny Piro, Diego Rosa, Michele Bevere, Peter Markus, Diana Behrens, Claudio Luchini, Rita T. Lawlor, Aldo Scarpa, Giulia Biffi, Phyllis F. Cheung, Jens T. Siveke and Vincenzo Corbo ()
Additional contact information
Lisa Veghini: University of Verona
Davide Pasini: University of Verona
Rui Fang: A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
Pietro Delfino: University of Verona
Dea Filippini: University of Verona
Christian Neander: A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
Caterina Vicentini: University of Verona
Elena Fiorini: University of Verona
Francesca Lupo: University of Verona
Sabrina L. D’Agosto: University of Verona
Carmine Carbone: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Antonio Agostini: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Geny Piro: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Diego Rosa: University of Verona
Michele Bevere: University and Hospital Trust of Verona
Peter Markus: Elisabeth Hospital Essen
Diana Behrens: EPO—Experimental Pharmacology and Oncology GmbH
Claudio Luchini: University of Verona
Rita T. Lawlor: University of Verona
Aldo Scarpa: University of Verona
Giulia Biffi: University of Cambridge
Phyllis F. Cheung: A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
Jens T. Siveke: A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
Vincenzo Corbo: University of Verona

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-β signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting myofibroblastic CAFs in vivo.

Date: 2024
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DOI: 10.1038/s41467-024-54975-8

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