Intercellular crosstalk between fibroblasts and breast cancer cells promotes tumor progression through the secretion of ESM1

In breast cancer (BC), stromal fibroblasts can be activated by tumour cells to differentiate into cancer-associated fibroblasts (CAFs), which promote tumour progression, metastasis, and invasion by secreting growth-promoting and proangiogenic factors [1]. The proteoglycan ESM1 (Endothelial cell-specific molecule 1) has been implicated in various pathological conditions, including cancer, where it is aberrantly expressed and contributes to cell proliferation, migration, and angiogenesis [2]. Based on this evidence, we investigated the role of ESM1 in a co-culture model of mammary fibroblasts and BC cells to clarify its involvement in tumour progression. Mammary fibroblasts were seeded in the lower chamber of a transwell system, while either MCF-7 (non-aggressive) or MDA-MB231 (aggressive) breast cancer cells were placed in the upper chamber. IL-1β was added to induce higher levels of fibroblast activation. Additional groups of fibroblasts were treated with either ESM1-specific siRNA or control siRNA. Co-culture with BC cells significantly increased ESM1 mRNA and protein levels in activated mammary fibroblasts. In parallel, BC cells exhibited elevated phosphorylation of AKT and ERK1/2, along with increased expression of cyclin D1, MMP-9, and vimentin —markers associated with proliferation, migration, and epithelial-mesenchymal transition. Notably, ESM1 knockdown in fibroblasts reduced all these parameters. These results suggest that ESM1 produced by activated fibroblasts plays a key role in enhancing breast cancer cell aggressiveness by modulating AKT and ERK signaling pathways and associated markers, indicating a novel mechanism through which the tumor microenvironment may drive tumour progression.