Journal Article

Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer

Agostini, Antonio, Cheung, Phyllis F., Veghini, Lisa, Pasini, Davide, Fang, Rui, Neander, Christian, D’Agosto, Sabrina L., Piro, Geny, Rosa, Diego, Filippini, Dea, Vicentini, Caterina, Fiorini, Elena, Carbone, Carmine, Scarpa, Aldo, Bevere, Michele, Markus, Peter, Behrens, Diana, Luchini, Claudio, Delfino, Pietro, Lupo, Francesca, Lawlor, Rita T., Biffi, Giulia, Corbo, Vincenzo, Siveke, Jens T.

2024

Overview

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 MAPK high 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. Phenotypic and functional heterogeneity of cancer associated fibroblasts (CAFs) has been reported in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that epithelial MAPK activity promotes myofibroblastic differentiation of CAFs. Furthermore, the epithelial basal-like subtype is associated with a CAF phenotype characterized by elevated MAPK activity and TGF-β signalling, associated with T cell exclusion in PDAC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/31 / 14/32 / 38/91 / 631/67/1504/1713 / 631/67/327 / 64/60 / 82/51 / Adenocarcinoma / Animal models / Animals / Cancer therapies / Cancer-Associated Fibroblasts - metabolism / Cancer-Associated Fibroblasts - pathology / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Carcinoma, Pancreatic Ductal - pathology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell culture / Cell Differentiation / Cell Line, Tumor / Fibroblasts / Gene Expression Regulation, Neoplastic / Genotype & phenotype / Heterogeneity / Human tissues / Humanities and Social Sciences / Humans / Hypoxia / Immune checkpoint inhibitors / Immunoregulation / Lymphocytes / Lymphocytes T / MAP kinase / MAP Kinase Signaling System / Melanoma / Mice / multidisciplinary / Myofibroblasts - metabolism / Myofibroblasts - pathology / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Phenotype / Phenotypes / Science / Science (multidisciplinary) / Signal transduction / Single-Cell Analysis / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b / Transforming growth factor-b1 / Tumor Microenvironment - genetics