Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

• Published in: Nature communications Vol. 12; no. 1; pp. 3516 - 17
• Main Authors: Jungwirth, Ute, van Weverwijk, Antoinette, Evans, Rachel J., Jenkins, Liam, Vicente, David, Alexander, John, Gao, Qiong, Haider, Syed, Iravani, Marjan, Isacke, Clare M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 14/19; 38; 38/91; 45; 45/23; 59/5; 631/67/1347; 631/67/322; 631/67/327; 631/80/304; 64/60; Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - secondary; Cancer; Cancer-Associated Fibroblasts - cytology; Cancer-Associated Fibroblasts - metabolism; Cell culture; Cell Proliferation - genetics; Cell Survival - genetics; Cells, Cultured; Coculture Techniques; Collagen; Contractility; Depletion; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Female; Fibroblasts; Heterogeneity; Humanities and Social Sciences; Humans; Impairment; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Knockout; Microenvironments; multidisciplinary; Neoplasm Metastasis; NIH 3T3 Cells; Phenotypes; Receptors; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Science; Science (multidisciplinary); Spheroids, Cellular - metabolism; Stroma; Stromal Cells - metabolism; Tumor microenvironment; Tumor Microenvironment - genetics; Tumor Stem Cell Assay; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23583-1

Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 ( MRC2 ) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation. Endo180, a collagen binding receptor, is highly expressed in a subset of cancer-associated fibroblasts. The authors show, using knockout mice and 3D in vitro assays, that Endo180 depletion impairs tumour fibroblast contractility and viability resulting in reduced tumour growth and metastasis.