Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54975-8 |
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| author | 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 Vincenzo Corbo |
| author_facet | 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 Vincenzo Corbo |
| author_sort | Lisa Veghini |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8561db064eef44aab4d075c66cf8b992 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8561db064eef44aab4d075c66cf8b9922025-08-20T02:20:41ZengNature PortfolioNature Communications2041-17232024-12-0115112010.1038/s41467-024-54975-8Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancerLisa Veghini0Davide Pasini1Rui Fang2Pietro Delfino3Dea Filippini4Christian Neander5Caterina Vicentini6Elena Fiorini7Francesca Lupo8Sabrina L. D’Agosto9Carmine Carbone10Antonio Agostini11Geny Piro12Diego Rosa13Michele Bevere14Peter Markus15Diana Behrens16Claudio Luchini17Rita T. Lawlor18Aldo Scarpa19Giulia Biffi20Phyllis F. Cheung21Jens T. Siveke22Vincenzo Corbo23Department of Engineering for Innovation Medicine, University of VeronaDepartment of Engineering for Innovation Medicine, University of VeronaDivision of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital EssenDepartment of Diagnostics and Public Health, University of VeronaDepartment of Diagnostics and Public Health, University of VeronaDivision of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital EssenDepartment of Diagnostics and Public Health, University of VeronaDepartment of Engineering for Innovation Medicine, University of VeronaDepartment of Engineering for Innovation Medicine, University of VeronaDepartment of Diagnostics and Public Health, University of VeronaDepartment of Medical and Surgical Sciences, Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Medical and Surgical Sciences, Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Medical and Surgical Sciences, Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Engineering for Innovation Medicine, University of VeronaARC-Net Research Centre, University and Hospital Trust of VeronaDepartment of General, Visceral, and Trauma Surgery, Elisabeth Hospital EssenEPO—Experimental Pharmacology and Oncology GmbHDepartment of Diagnostics and Public Health, University of VeronaDepartment of Engineering for Innovation Medicine, University of VeronaDepartment of Diagnostics and Public Health, University of VeronaCancer Research UK Cambridge Institute, University of CambridgeDivision of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital EssenDivision of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital EssenDepartment of Engineering for Innovation Medicine, University of VeronaAbstract 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.https://doi.org/10.1038/s41467-024-54975-8 |
| spellingShingle | 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 Vincenzo Corbo Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer Nature Communications |
| title | Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer |
| title_full | Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer |
| title_fullStr | Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer |
| title_full_unstemmed | Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer |
| title_short | Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer |
| title_sort | differential activity of mapk signalling defines fibroblast subtypes in pancreatic cancer |
| url | https://doi.org/10.1038/s41467-024-54975-8 |
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