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

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 remodelling 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. Using single-cell RNA sequencing of breast cancer organoids, we identified a basal-like leader cell subset enriched for cytoskeletal, ECM-remodelling, and epithelial junction genes. We show that integrin α2 (Itgα2) links collagen I engagement to mesenchymal reprogramming by inducing Inhba expression and activating TGFβ signalling. This, in turn, upregulates Vimentin while preserving epithelial junction gene expression. In parallel, Itgα2 promotes ECM degradation through a TGFβ-independent mechanism. This dual mechanism supports a model of partial EMT as a regulated state and highlights the Itgα2-TGFβ axis as a potential therapeutic target in aggressive breast cancers.