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.

• Authors: Elvira Infante, Alessia Castagnino, Robin Ferrari, Pedro Monteiro, Sonia Agüera-González, Perrine Paul-Gilloteaux, Mélanie J Domingues, Paolo Maiuri, Matthew Raab, Catherine M Shanahan, Alexandre Baffet, Matthieu Piel, Edgar R Gomes, Philippe Chavrier
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 2443 (06 22 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29934494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• LMNA protein, human
• Lamin Type A
• Microfilament Proteins
• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• SYNE2 protein, human
• 1-Alkyl-2-acetylglycerophosphocholine Esterase
• PAFAH1B1 protein, human
• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase (metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Nucleus (metabolism)
• Centrosome (metabolism)
• Humans
• Lamin Type A (metabolism)
• Matrix Metalloproteinase 14 (metabolism)
• Microfilament Proteins (metabolism)
• Microtubule-Associated Proteins (metabolism)
• Neoplasm Invasiveness (pathology)
• Neoplasms (pathology)
• Nerve Tissue Proteins (metabolism)
• Nuclear Proteins (metabolism)
• Podosomes (metabolism)
• Proteolysis