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

By M. Bartoschek, N. Oskolkov, M. Bocci, J. Lövrot, C. Larsson, M. Sommarin, C. Madsen, David Lindgren, G. Pekar, G. Karlsson and 4 more. Nature Communications, 2018

694 citations recorded by the source corpus.

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. Cancer-associated fibroblasts (CAFs) are an important component of the breast tumour microenvironment. Here, single-cell RNA sequencing of CAFs from a mouse model of breast cancer defines three transcriptomically distinct subpopulations with putatively different functions.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/38605ba24e558ec1ac0699076878159c3956af0a

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In Molecular Biology

1. Qingxiang Zeng
2. Junjiang Liu
3. Jin Yang
4. J. Mu
5. Shuzhi Deng
6. Fanglong Wu
7. Ye Wang
8. Hongmei Zhou

Citations in the corpus

• Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “dCAFs SCRG1 (malignant cells) Not reported [100]”
• Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. (2020, background): “The first single-cell data on CAFs from human cancers and mouse models confirmed the existence of ECM-rich (CAF-S1) and contractile (CAF-S4) subpopulations (16, 24, 26, 29, 38), indicating that CAF-S1 and CAF-S4 can be detected in distinct cancer types and across species.”
• Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer (2021, background): “In a mouse model of breast cancer, three transcriptionally diverse subpopulations of CAFs were defined via various lineage sources.(57) In addition, the cues emanating from molecular phenotypes or secretion phenotypes might also determine the CAFs’ heterogeneity.”