Increased Meflin Expression in Cancer-Associated Fibroblasts Restrains Tumor Cell Proliferation and Shapes Vessel-Rich Stroma in Triple-Negative Breast Cancer

Recent studies have shown that cancer-associated fibroblasts (CAFs), a key component of the tumor microenvironment, are heterogeneous and can be divided into distinct subsets. Although all CAFs were believed to promote tumor progression, recent studies have identified a distinguished subset of tumor-restraining CAFs (rCAFs). It was previously demonstrated that the up-regulation of Meflin (immunoglobulin superfamily containing leucine-rich repeat) expression confers a tumor-restraining role on CAFs in pancreatic, colon, urothelial, and lung cancers. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a poor prognosis. In this study, it was shown that Meflin can be a candidate marker for rCAFs in TNBC. In co-culture experiments with tumor cells and fibroblasts, Meflin overexpression in fibroblasts inhibited tumor cell growth in a three-dimensional culture model and shifted their gene expression profile toward that characteristic of universal or normal fibroblasts. Meflin overexpression in fibroblasts significantly reduced the expression of the chemokine receptor ACKR3 and enhanced that of the prostaglandin synthase PTGDS. This is suggestive of the involvement of these proteins in tumor microenvironment regulation. Furthermore, Meflin deficiency reduced the area of tumor vessels in a TNBC mouse model, highlighting its role in CAF-mediated inhibition of TNBC progression and improvement of drug delivery. Accordingly, Meflin plays a role as a potential functional marker of rCAFs in TNBC.