Samenvatting

The primary cause of death in breast cancer cases is often metastasis, the spread of cancer cells systemically and the formation of secondary tumors in distant organs of the body. The invasion of breast tumor cells into the surrounding tissue is an initial step in the metastatic cascade. In addition to the various breast cells, the tissue constitutes of an intricate network of proteins and other elements known as the extracellular matrix (ECM). The breast cancer tumor cells can recognize and adhere to specific components of the ECM, with collagen I being the predominant element in the breast ECM. The typical mode of spread into the surrounding ECM is collective invasion, where breast cancer tumors advance as a cohesive multicellular group. This collective invasion is orchestrated by few cells known as the leader cells, possessing unique characteristics. Leader cells emerge from a specific subset of cells called basal-like cells, already present at the boundary between the tumor and the ECM before their transition into leaders. The reason in which these basal-like cells localize at the tumor-ECM interface remains elusive. In this study we uncover the role of collagen I and its receptor integrin alpha 2 (ITGα2) in the positioning of basal-like cells and their transitioning into leaders guiding the collective movement. We propose that ITGα2 regulates the
interplay between the remodeling of the ECM and the paracrine signaling, whereby ITGα2 induces the expression of the TGF-β ligand Inhβa causing the formation of leader cells and initiating collective invasion in collagen I.