Integrin-TGFb axis induces partial EMT in basal-like cells to lead collective invasion

Abstract

Collective invasion is the predominant mode of cancer cell dissemination in breast cancer and represents the initial step of metastatic spread. Basal-like leader cells drive this process by maintaining cell-cell junctions with the follower cells while extending actin-rich protrusions and remodeling the collagen I-rich peritumoral stroma. These features resemble those of individually-invading cells following epithelial-to-mesenchymal transition (EMT). However, how leader cells acquire these traits while preserving cohesion within the collective remains unclear. Here, we identify a collagen I-responsive subset of basal-like cells that coexpress cytoskeletal, extracellular matrix (ECM)-remodeling, and epithelial junction genes. We show that integrin 2 (Itg2) links collagen I engagement to mesenchymal reprogramming by inducing inhibin beta A (INHBA) expression and activating tumor growth factor {beta} (TGF{beta}) signaling. This, in turn, upregulates vimentin while preserving epithelial junction gene expression. In parallel, Itg2 promotes ECM degradation through a TGF{beta}-independent mechanism. This study identifies Itg2-TGF{beta} axis as a key regulator of partial EMT and leader cell function, highlighting it as a potential therapeutic target in aggressive breast cancers.