8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
Squish and squeeze – the role of the nucleus and lamins in cancer metastasis
Weill Institute for Cell & Molecular Biology, Department of Biomedical Engineering, Cornell University, 235 Weill Hall Ithaca, NY 14853-7202, USA
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During cancer cell invasion and metastasis, cancer cells migrate through interstitial spaces and transendothelial openings as small as 2 µm in diameter. The deformability of the large and relatively rigid cell nucleus constitutes a rate-limiting factor in the passage of cells through such confined environments. Since the nuclear envelope proteins lamins A and C are a major determinant of nuclear deformability and their expression is misregulated in many cancers, we examined whether reduced levels of lamin A/C correlated with increased nuclear deformability, increased invasion potential in confined environments, and an increased risk of disease progression in breast cancer. Patient-derived breast tumor tissues and cell lines had significantly lower lamin A levels than normal tissues, and particularly metastatic cell lines had significantly lower levels of lamin A/C than less aggressive cancer cell lines. Levels of lamin A/C inversely correlated with nuclear deformability, with claudin-low subtype cells exhibiting the lowest levels of lamin A/C and the highest nuclear deformability. Breast cancer cells with low levels of lamin A/C migrated faster through micron-scale microfluidic constrictions and dense collagen matrices than cells with high levels of lamin A/C. Increasing expression of lamin A in breast cancer cells with normally low levels of lamin A/C significantly impaired their invasive properties, while depletion of lamin A/C in cells with normally high levels of lamin A/C increased their invasive potential. Increasing lamin A expression in metastatic cells also decreased cell proliferation and altered expression of several cell adhesion proteins, extracellular matrix proteins, and regulators of cell metabolism, as revealed by stable isotope labeling with amino acids in cell culture (SILAC) mass spectroscopy analysis, suggesting additional pathways by which lamins impact cancer cell invasion and disease progression. These studies indicate that downregulation of A-type lamin levels in breast cancer cells could coordinate both tumor cell invasion and outgrowth, thus providing an important point of control over the development of metastases. Insights gained from these studies could improve current diagnostic and prognostic approaches. Ultimately, targeting newly identified regulator pathways affected by altered lamin expression could offer novel therapeutic avenues to control metastatic disease in breast cancer.