Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness

Abstract

Micronuclei (MN) can arise from many causes, including the breakage of aberrant cytokinetic chromatin bridge. The frequent observation of MN in tumors raises the specter that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we propose a mechanism that the presence of micronuclei could induce specific phenotypic and functional changes to the cell and lead to increased cancer invasive potential. Through the integration of diverse imaging and molecular techniques in vitro, supported by clinical samples from D’Amico high-risk prostate cancer (PCa) patients, our study demonstrates that the resolution of chromosome bridges can result in the accumulation of EMD and the formation of EMD-rich MN. Such structure is negative for Lamin A/C, positive for Lamin-B receptor and Sec61β. It can act as a protein sink and result in EMD pauperization from the nuclear envelope. The phenotype of emerin mis-localization is associated with molecular signature that correlates to worse prognosis in PCa and is enriched in metastatic samples. Emerin mis-localization corresponds with migratory and invasive properties of tumor cells, especially in the context collagen-rich microenvironment. Our study demonstrates that the mis-localization of emerin to MN induces increased cell invasiveness, thereby exacerbating patient’s prognosis.