Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer
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<sup>high</sup> CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8<sup>+</sup> 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.
Authors
- Aldo Scarpa
- Carmine Carbone (ORCID: https://orcid.org/0000-0001-5168-747X)
- Rui Fang (ORCID: https://orcid.org/0000-0001-6075-9201)
- Vincenzo Corbo (ORCID: https://orcid.org/0000-0002-6340-8009)
- Caterina Vicentini (ORCID: https://orcid.org/0000-0003-2231-2147)
- Christian Neander
- Diana Behrens
- Rita T. Lawlor (ORCID: https://orcid.org/0000-0003-3160-0634)
- Geny Piro (ORCID: https://orcid.org/0000-0003-3708-5397)
- Antonio De Agostini (ORCID: https://orcid.org/0000-0002-3910-0223)
- Claudio Luchini (ORCID: https://orcid.org/0000-0003-4901-4908)
- Davide Pasini (ORCID: https://orcid.org/0000-0002-8270-7143)
- Phyllis F. Cheung (ORCID: https://orcid.org/0000-0002-0075-5679)
- Elena Fiorini (ORCID: https://orcid.org/0000-0002-9693-6094)
- Giulia Biffi (ORCID: https://orcid.org/0000-0003-4592-0970)
- Lisa Veghini (ORCID: https://orcid.org/0000-0003-3289-1189)
- Jens Thomas Siveke (ORCID: https://orcid.org/0000-0002-8772-4778)
- Dea Filippini (ORCID: https://orcid.org/0000-0002-4792-613X)
- Michele Bevere (ORCID: https://orcid.org/0000-0001-8778-0860)
- Pietro Delfino (ORCID: https://orcid.org/0000-0003-0119-0830)
- P. M. Markus
- Sabrina L. D’Agosto
- D.D. Rosa
- Francesca Lupo
Institutions
- University of Verona (IT)
- Vita-Salute San Raffaele University (IT)
- German Cancer Research Center (DE)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Agostino Gemelli University Polyclinic (IT)
- Elisabeth-Krankenhaus Essen (DE)
- Essen University Hospital (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-54975-8
- Citations
- 20
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 5.65
Funders
- Government of Ontario
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Associazione Italiana per la Ricerca sul Cancro
- Università degli Studi di Verona
- Deutschen Konsortium für Translationale Krebsforschung
- Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
- National Cancer Institute