CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

Julia M. Houthuijzen (), Roebi Bruijn, Eline Burg, Anne Paulien Drenth, Ellen Wientjens, Tamara Filipovic, Esme Bullock, Chiara S. Brambillasca, Emilia M. Pulver, Marja Nieuwland, Iris Rink, Frank Diepen, Sjoerd Klarenbeek, Ron Kerkhoven, Valerie G. Brunton, Colinda L.G.J. Scheele, Mirjam C. Boelens and Jos Jonkers ()
Additional contact information
Julia M. Houthuijzen: The Netherlands Cancer Institute
Roebi Bruijn: The Netherlands Cancer Institute
Eline Burg: The Netherlands Cancer Institute
Anne Paulien Drenth: The Netherlands Cancer Institute
Ellen Wientjens: The Netherlands Cancer Institute
Tamara Filipovic: The Netherlands Cancer Institute
Esme Bullock: University of Edinburgh
Chiara S. Brambillasca: The Netherlands Cancer Institute
Emilia M. Pulver: The Netherlands Cancer Institute
Marja Nieuwland: Genomics Core Facility, The Netherlands Cancer Institute
Iris Rink: Genomics Core Facility, The Netherlands Cancer Institute
Frank Diepen: Flow Cytometry Facility, The Netherlands Cancer Institute
Sjoerd Klarenbeek: The Netherlands Cancer Institute
Ron Kerkhoven: Genomics Core Facility, The Netherlands Cancer Institute
Valerie G. Brunton: University of Edinburgh
Colinda L.G.J. Scheele: VIB Center for Cancer Biology, KU Leuven
Mirjam C. Boelens: The Netherlands Cancer Institute
Jos Jonkers: The Netherlands Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice, we show that CAFs in both invasive lobular breast cancer and triple-negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo and in vitro studies reveal the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. Functional co-culture experiments show that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data suggest that CD26+ and CD26- NFs transform into distinct CAF subpopulations in mouse models of breast cancer.

Date: 2023
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DOI: 10.1038/s41467-023-35793-w

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