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         description:Cancer cells’ ability to migrate through constricting pores in the tissue matrix is limited by nuclear stiffness. MT1-MMP contributes to metastasis by widening matrix pores, facilitating confined migration. Here, we show that modulation of matrix pore size or of lamin A expression known to modulate nuclear stiffness directly impinges on levels of MT1-MMP-mediated pericellular collagenolysis by cancer cells. A component of this adaptive response is the centrosome-centered distribution of MT1-MMP intracellular storage compartments ahead of the nucleus. We further show that this response, including invadopodia formation in association with confining matrix fibrils, requires an intact connection between the nucleus and the centrosome via the linker of nucleoskeleton and cytoskeleton (LINC) complex protein nesprin-2 and dynein adaptor Lis1. Our results uncover a digest-on-demand strategy for nuclear translocation through constricted spaces whereby confined migration triggers polarization of MT1-MMP storage compartments and matrix proteolysis in front of the nucleus depending on nucleus-microtubule linkage. The ability of cancer cells to migrate through small, constricted areas is limited by nuclear stiffness. Here the authors show that in turn nuclear stiffness stimulates the delivery of enzymes important for the degradation of the extracellular matrix and the formation of invadopodia in association with fibers thus opposing nuclear movement.
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      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
      name:Institut Curie, PSL Research University, Paris, France
      name:BHF Centre of Research Excellence, Cardiovascular Division, King’s College, London, UK
      name:Institut Curie, PSL Research University, Paris, France
      name:Institut Curie, PSL Research University, Paris, France
      name:Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
      name:Institut Curie, PSL Research University, Paris, France

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