The role of LAP1 isoform balance in regulating nuclear plasticity during confined cancer cell migration

Metastasis, which accounts for the majority of cancer-related deaths, requires cells to squeeze through narrow extracellular spaces, where the stiffness of the nucleus becomes a major physical barrier. This nuclear deformability is largely governed by nuclear envelope (NE) proteins, including lamina-associated polypeptide 1 (LAP1). LAP1, encoded by TOR1AIP1 , exists as two isoforms generated from alternative translation start sites: the longer LAP1B, which binds tightly to the nuclear lamina and stabilizes the nucleus, and the shorter LAP1C, which interacts more loosely and promotes nuclear flexibility. Transcriptomic profiling of patient-derived melanoma cell line pairs revealed elevated LAP1 expression in more metastatic cells, with a higher LAP1C:LAP1B ratio associated with increased migratory potential.To dissect the functional consequences of this ratio, we generated stable melanoma cell lines overexpressing mRuby-tagged LAP1B, LAP1C, or wild-type LAP1 via retroviral transduction. Expression and localization were confirmed by immunofluorescence and Western blotting. We then assessed cell motility using transwell migration assays to mimic the mechanical constraints of tissue invasion. We demonstrated that LAP1C overexpression significantly enhanced migration, while LAP1B reduced it, without affecting nuclear morphology or actomyosin contractility. These findings suggest that LAP1 directly regulates nuclear plasticity to enable movement through confined environments.Preliminary data indicate that cellular stress can alter the LAP1C:LAP1B ratio, suggesting that isoform switching may be a regulated adaptive mechanism. This suggests that changes in the tumour microenvironment such as metabolic stress could influence nuclear mechanics through differential LAP1 expression.Strikingly, we found that primary immune and leukemia cells exclusively express the shorter LAP1C isoform, implying that the absence of LAP1B may facilitate their rapid amoeboid migration through dense tissues. Future work will explore how LAP1 isoform regulation supports leukemia cell motility in confined migration, providing broader insight into how nuclear envelope composition shapes cancer cell invasiveness.