Editors' ChoiceCancer

Not all fibroblasts are equal in cancer

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Science Translational Medicine  05 Aug 2020:
Vol. 12, Issue 555, eabd4769
DOI: 10.1126/scitranslmed.abd4769

Abstract

The ratio of two cancer-associated fibroblast subpopulations with distinct functions affects breast cancer clinical outcomes.

Cancer-associated fibroblasts (CAFs) regulate multiple cancer processes, including sustained growth, invasion, inflammation, and immunosuppression. Recent studies have investigated their origin and begun to discover cell surface markers uniquely expressed in CAFs. However, it is unclear how CAF supopulations evolve during tumor progression and whether CAFs can serve as prognostic biomarkers of disease outcomes.

Friedman et al. used single-cell RNA sequencing and the cell surface marker podoplanin (PDPN) in an immunocompetent breast cancer model and discovered two major CAF clusters, pCAFs (PDPN+) and sCAFs (PDPN- and cytoplasmic fibroblast-specific protein S100A4+). The fraction of pCAFs decreased as tumors progressed from 70% of total CAFs at 2 weeks after tumor injection to 23% at 4 weeks. pCAFs were more heterogeneous transcriptionally, with six subsets expressing wound healing, extracellular matrix (ECM), inflammatory A/B, and immune-regulatory signatures E/L, although sCAFs included two subsets expressing an antigen-presenting and a protein-folding signature. Cell lineage pseudo-time analysis showed that pCAFs likely originated from normal breast fibroblasts, whereas sCAFs expressed several mesenchymal stem cell (MSC) markers, suggesting that they likely originate from bone marrow–derived MSCs. In situ immunofluorescence staining for PDPN, S100A4, and an epithelial marker confirmed the presence of distinct pCAF and sCAF subpopulations in two immunocompetent murine models and in human breast carcinomas. Functional coculture experiments demonstrated that one subpopulation of pCAFs suppressed T cell proliferation. Importantly, a high ratio of S100A4/PDPN expression by immunostaining, reflecting an increased fraction of pCAFs compared to sCAFs, was associated with poor outcomes in two independent cohorts of breast cancer patients.

These findings on the functional heterogeneity of CAFs highlight the complexity and dynamic reprogramming in the breast tumor microenvironment. Future studies are needed to identify treatment strategies that would decrease the fraction of immunosuppressive pCAFs. This is a critical issue, particularly in the aggressive triple-negative breast cancer subtype, where a high pCAF/sCAF ratio is associated with cancer-promoting mutations, and new therapeutic options are urgently needed. Finally, a better understanding of whether these genomically stable CAF supopulations are associated with differential responses to cancer therapies could reveal opportunities for personalizing therapies.

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