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.

The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.

Details

Title
CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer
Author
Houthuijzen, Julia M. 1   VIAFID ORCID Logo  ; de Bruijn, Roebi 2 ; van der Burg, Eline 1 ; Drenth, Anne Paulien 1 ; Wientjens, Ellen 1 ; Filipovic, Tamara 1 ; Bullock, Esme 3 ; Brambillasca, Chiara S. 1 ; Pulver, Emilia M. 1   VIAFID ORCID Logo  ; Nieuwland, Marja 4 ; de Rink, Iris 4 ; van Diepen, Frank 5 ; Klarenbeek, Sjoerd 6   VIAFID ORCID Logo  ; Kerkhoven, Ron 4 ; Brunton, Valerie G. 3   VIAFID ORCID Logo  ; Scheele, Colinda L.G.J. 7   VIAFID ORCID Logo  ; Boelens, Mirjam C. 1 ; Jonkers, Jos 1   VIAFID ORCID Logo 

1  The Netherlands Cancer Institute, Division of Molecular Pathology, Oncode Institute, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393) 
2  The Netherlands Cancer Institute, Division of Molecular Pathology, Oncode Institute, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393); The Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393) 
3  University of Edinburgh, Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
4  Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393) 
5  Flow Cytometry Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393) 
6  The Netherlands Cancer Institute, Experimental Animal Pathology Facility, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393) 
7  VIB Center for Cancer Biology, KU Leuven, Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Leuven, Belgium (GRID:grid.511459.d); Department of Oncology, KU Leuven, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
Pages
183
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-35793-w
ProQuest document ID
2764898568
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.