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Characterization of the MT1-MMP/invadopodia axis during breast cancer cells invasion in type I collagen

Abstract : Tumor invasion and distant metastasis are leading causes of cancer-related death. Cancer invasive program requires tumor cells to transmigrate through the basement membrane and invade through type I fibrous collagen networks, which act as physical barriers opposing cell movement. Cancer cell migration into constricting pores is limited by nuclear stiffness and deformability and necessitates proteolytic remodeling of extracellular matrix (ECM) components by metalloproteinases (MMPs). In particular, membrane-tethered 1 (MT1)-MMP exocytosis in specialized actin-rich structures called invadopodia allows pericellular proteolysis to widen matrix pores and facilitate nuclear transmigration. However, whether and how invasive cells coordinate mechanical cues from the environment with invadopodia formation, localization and function in matrix degradation is unknown. In my PhD work, I showed that confined migration into fibrillar collagen networks triggers polarization of MT1-MMP storage compartments and invadopodia-based pericellular collagenolysis in front of the nucleus. Modulation of either matrix pore size or nuclear stiffness interferes with this adaptive response indicating that invasive cells adapt MT1-MMP-mediated ECM proteolysis to matrix confinement levels in a “digest-on-demand” strategy. I further showed that actin polymerization in invadopodia structures produced forces which are transmitted to and push aside the underlying collagen fibers enabling matrix pore widening. Overall, these findings define a new role for invadopodia as proteolytic contacts that combine actin-driven force production and matrix-cleavage activity to facilitate path clearance for invasion.
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Submitted on : Monday, February 15, 2021 - 11:18:26 AM
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Robin Ferrari. Characterization of the MT1-MMP/invadopodia axis during breast cancer cells invasion in type I collagen. Cellular Biology. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS098⟩. ⟨tel-03141340⟩

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