Systematic Analysis of the Functional Relevance of Nuclear Structure and Mechanics in Breast Cancer Progression

Abstract

Abstract : Abnormal nuclear shape and structure has long been recognized as a characteristic feature of cancer cells, but the underlying molecular basis and functional consequences have remained elusive. It is now emerging that many breast cancer cells have reduced expression of lamins A/C, which negatively correlates with disease-free survival. To investigate the consequences of altered lamin expression in more detail, we modulated the expression of lamins in a panel of breast cancer cells. By developing and using novel microfluidic devices that mimic the conditions encountered during perfusion through capillaries or migration through interstitial spaces, we demonstrated that nuclear deformability, governed by levels of lamins A/C, constitutes a rate-limiting factor in the ability of cells to pass through openings smaller than the nucleus. Furthermore, we found that metastatic cells can dynamically adjust their nuclear envelope composition during migration through confining 3-D environments, facilitating transit through narrow constrictions. Interestingly, cells with reduced levels of lamins A/C were more prone to repetitive nuclear rupture, which could result in increased DNA damage and chromosomal rearrangements. Loss of lamins A/C also disturbed MKL1/SRF signaling. Our findings could provide novel diagnostic and prognostic markers for the treatment of cancer patients; ultimately, a better understanding of the molecular mechanisms underlying the ability of breast cancer cells to dynamically alter their nuclear envelope composition may lead to the identification of new therapeutic targets.