Fig. 9

Model of actin-based proteolytic contacts during the early phases of the tissue-invasive cascade. a Tumor cells plated on top of a layer of fibrillar type I collagen form semi- to fully circular proteolytic contacts along collagen fibrils upon recognition of the collagen fibers by surface-exposed MT1-MMP, which correspond to invadopodia. Arp2/3 complex-mediated invadopodial actin assembly generates pushing forces against the collagen fibers, resulting in displacement of invadopodia-associated collagen fibers and matrix pore opening underneath the cell body. Due to the limited thickness of the collagen layer in this experimental setup (5–10 µm), cell invasion is impaired. b Confined migration of tumor cells through the dense 3D collagen network triggers invadopodia formation along collagen fibers, which constrict the nucleus^9,18. MT1-MMP-mediated collagenolysis together with actin-driven force production cause matrix pore enlargement to promote nuclear transmigration and cell invasion. c Sketch of the physical model representing the invadopodial actin filament meshwork pushing on the collagen fiber (see Supplementary Figure 8 in Supplementary Note 1). Due to the curvature of the invadopodia/collagen-fiber ensemble, actin filaments are polymerizing and growing against their neighbors, therefore generating a force directed toward the collagen fiber that can further push, deform and displace the constricting fiber. This is potentiated by MT1-MMP proteolytic activity which lower collagen fiber bending energy and counter-resistance to this force. d We propose the following model of the early phases of the tissue-invasive cascade of carcinoma cells. Tumor invasion starts with the transmigration of the carcinoma cell through the basement membrane that involves MT1-MMP-mediated matrix proteolysis^10,11. Small individual invadopodia producing focal basement membrane degradation may coalesce into a single ring-like structure at the interface between the cell and the quasi-2D basement membrane. Actin-based force generation at the ring-like invadopodia structure may help tear the basement membrane apart and widen the transmigration pore, which is then used by the cancer cell to project the invasive protrusion. In carcinomas, some emerging collective behaviors may induce a large area of basement membrane degradation (not drawn for simplicity). Once tumor cells reach the type I collagen-rich interstitial environment, proteolytic contacts form and promote cell invasion