Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing

Michael Bartoschek, Nikolay Oskolkov, Matteo Bocci, John Lövrot, Christer Larsson, Mikael Sommarin, Chris D. Madsen, David Lindgren, Gyula Pekar, Göran Karlsson, Markus Ringnér, Jonas Bergh, Åsa Björklund and Kristian Pietras ()
Additional contact information
Michael Bartoschek: Lund University
Nikolay Oskolkov: Lund University
Matteo Bocci: Lund University
John Lövrot: Karolinska Institutet
Christer Larsson: Lund University
Mikael Sommarin: Lund University
Chris D. Madsen: Lund University
David Lindgren: Lund University
Gyula Pekar: Skåne University Hospital
Göran Karlsson: Lund University
Markus Ringnér: Lund University
Jonas Bergh: Karolinska Institutet
Åsa Björklund: Uppsala University
Kristian Pietras: Lund University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs.

Date: 2018
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DOI: 10.1038/s41467-018-07582-3

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