How impairment of cancer-associated fibroblast subset alters breast cancer microenvironment and reduces tumour growth and metastasis

Over the recent years several studies have revealed a substantial heterogeneity in cancer-associated fibroblasts (CAFs) in the tumour microenvironment. Functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. In this study we demonstrate that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a subset of matrix remodelling CAFs, but not tumour cells, profoundly limits breast cancer growth and metastasis in vivo. These findings can be recapitulated in vitro in 3D co-culture assays. The impairment of breast cancer progression results from a CAF-intrinsic contractility defect and reduced CAF viability, manifesting in reduced numbers of alphaSMA-positive CAFs in tumours. Together, with the lack of a phenotype in the non-tumourbearing mouse, it demonstrates that upregulated Endo180 expression by a specific CAF subset is required to generate a supportive tumour microenvironment. Characterisation of a breast cancer subline, selected via serial in vivo passage for its ability to metastasise and overcome these stromal defects, provides evidence how CAF inhibition can drive tumour evolution resulting in subclones with enhanced intrinsic matrix remodelling properties. Together these data support the critical role played by the microenvironment in driving tumour evolution but, more importantly, highlight the potential advantages of taking a more selective therapeutic approach of targeting a specific CAF subset to limit disease progression.