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Nat Commun. 2018 Dec 4;9(1):5150. doi: 10.1038/s41467-018-07582-3.

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

Author information

1
Division of Translational Cancer Research, Department of Laboratory Medicine, BioCARE, Lund University, Medicon Village, 22381, Lund, Sweden.
2
Department of Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University, Sölvegatan 35, 22362, Lund, Sweden.
3
Department of Oncology and Pathology, Karolinska Institutet, Karolinska Universititetssjukhuset Z1:01, 17176, Stockholm, Sweden.
4
Division of Molecular Hematology, Lund Stem Cell Center, Lund University, BMC B12, 22184, Lund, Sweden.
5
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Skåne University Hospital, 22185, Lund, Sweden.
6
Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Husargatan 3, 75237, Uppsala, Sweden.
7
Division of Translational Cancer Research, Department of Laboratory Medicine, BioCARE, Lund University, Medicon Village, 22381, Lund, Sweden. Kristian.Pietras@med.lu.se.

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.

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