Abstract
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.
Highlights
Cancer cells’ ability to migrate through constricting pores in the tissue matrix is limited by nuclear stiffness
We provide evidence that endosome polarization and membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent collagenolysis require integrity of the linker of nucleoskeleton and cytoskeleton (LINC) complex that connects the nuclear lamina to cytoskeletal elements in the cytoplasm and the dynein regulator Lis[1] involved in nucleusmicrotubule cytoskeleton linkage[19]
Several converging studies revealed that nuclear stiffness and nuclear deformability are critical factors that limit confined cell migration through adjacent tissue and basement membrane transmigration by carcinoma cells[1,2,3,4,7]
Summary
Cancer cells’ ability to migrate through constricting pores in the tissue matrix is limited by nuclear stiffness. In cells invading through the small pore size collagen gel, MT1-MMP-containing endosomes clustered in a region anterior to the nucleus relative to the direction of movement (Fig. 2a and Supplementary Movie 1); The centrosome is positioned ahead of the nucleus.
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