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

Abstract

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.

Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities

“…This assumption was supported by another study conducted by Jungwirth et al . [43]. They proved that Endo180 (MRC2) was essential for CAFs to promote breast cancer metastasis, and Endo180‐positive CAFs substantially overlapped with mCAFs in the study by Bartoschek et al .…”

“…Fibronectin is abundant in breast cancer, and CAFs continuously secrete fibronectin upon stimulation with TGF-β and interferon gamma (IFN-γ) released by the tumor [274,275]. CAFs not only increase the expression of fibronectin but also alter its arrangement and promote the migration of tumor cells [43,276]. In breast cancer, the expression of fibronectin was associated with shorter patient survival [277].…”

Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

“…As a recent example of the functional significance of ECM-related proteins in breast cancer CAFs, siRNA-based knockdown of the endocytic receptor uPARAP (Endo180), which endocytoses both native and denatured collagens, in mouse mammary tumor TGF-β-inducible CAFs, resulted in reduced CAF viability and contraction and limited mammary tumor growth and metastasis (Jungwirth et al 2021 ). In another example breast carcinoma cell-secreted matricellular protein osteopontin (OPN) was shown to stimulate CAFs to differentiate into a migratory and collagen-producing myofibroblast tumor-promoting phenotype in a CD44- and-αvβ3-dependent manner (Sharon et al 2015 ).…”

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

“…Nonetheless, it is not yet clear whether all CAFs contribute to the metastatic dissemination of PDAC cells. One group identified a population of matrix-remodeling CAFs expressing the Endo180 ( MRC2 ) receptor that supported tumor growth and metastasis ( Jungwirth et al, 2021 ).…”