LINC complex-Lis1 interplay controls MT1-MMP matrix digest-on-demand response for confined tumor cell migration

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.

Reconstitution of cell migration at a glance

“…In contrast, on wider lines, they occupy a location at the front of the nucleus, as previously reported for mesenchymal cells (Bettinger et al, 2009;Doyle et al, 2009). The functional significance of this polarity switch is still largely unknown, but might be relevant in cancer cells to allow matrix degradation in front of the nucleus (Infante et al, 2018;Kim et al, 2010). Interestingly, migration on thin lines has been shown to promote a motility mode similar to the one observed in 3D microenvironments, indicating that this system could be used as a simplified tool for the study of mechanisms controlling cell migration in more complex microenvironments (Doyle et al, 2009;Karuri et al, 2004;Teixeira et al, 2003).…”

“…Migrating single cells, especially mesenchymal cells like fibroblasts and some tumor cells, can move along thin fibers (Harrison, 1911;Infante et al, 2018) and other tracks in tissues and in reconstituted matrices (Doyle et al, 2009;Elkhatib et al, 2017;Schumann et al, 2010). This phenomenon can be mimicked with minimal systems such as suspended fibers (Guetta-Terrier et al, 2015;Janson and Putnam, 2015) or by using thin printed lines of adhesive molecules on a 2D substrate (Clark and Vignjevic, 2015;Doyle et al, 2009) (see poster).…”

Compromised nuclear envelope integrity drives tumor cell invasion

“…Collagen degradation is also a requirement in the DCIS intraductal xenograft tumor model for the transition from in situ-to-invasive carcinoma ( 17,18 ). We thus assessed the collagen degradation activity of DCIS cells embedded into a 3D type I collagen matrix for 12 h and stained with an antibody that specifically recognizes the collagenase-cleaved ¾ fragment of collagen I ( 17,33,34 ). Importantly, cells were treated with drugs, or confined for several hours, and then were embedded in the 3D collagen gel in the absence of any further DNA damaging condition.…”

Lamin B2 follows lamin A/C- mediated nuclear mechanics and cancer cell invasion efficacy

“…In addition, lamin A expression, often measured as lamin A:B ratio, positively correlated with ECM rigidity , indicating lamin A as the main structure mediating resistance to deformation force. Accordingly, migrating rates of nontransformed fibroblasts and invasive cancer cells in confining substrates in vitro, such as collagen, PDMS channels or transwell chambers, depend on the expression level of lamin A/C (Davidson et al, 2014;Greiner et al, 2014;Harada et al, 2014;Infante et al, 2018;Lautscham et al, 2015;Ribeiro et al, 2014;Rowat et al, 2013;Shin et al, 2013;Yadav et al, 2018), in line with findings that softer tumor cells associate with higher invasion rates (Swaminathan et al, 2011). With cancer progression, the de-differentiation of tumor cells and acquisition of stem cell properties is often accompanied by de-regulated A-as well as B-type lamin expression (Alhudiri et al, 2019;Broers J.L.V., 2014;Chow et al, 2012;Denais and Lammerding, 2014;Saarinen et al, 2015;Wazir et al, 2013).…”