Nuclear envelope remodelling during constrained migration of melanoma cells

Student thesis: Doctoral ThesisDoctor of Philosophy


The nuclear envelope (NE) provides a biological and physical connection for the cell nucleus to sense and adapt during migration, but when the NE holds structural defects and gets overstimulated it can undergo rupture, which threatens genomic stability and cell survival. The nuclear lamina and chromatin enable nuclear deformability while nucleocytoplasmic recompartmentalisation restores nuclear integrity. However, little is known about how tumour cells exploit NE resilience to boost migration through tight spaces during metastasis.

Using melanoma as a working model, this research unravels molecular mechanisms for NE remodelling that support disease progression. First, multi-round transwell migration assays revealed that high Rho-ROCK1/2-driven actomyosin contractility provides the adaptability required for metastatic melanoma cells to squeeze their nuclei through constraints. Second, it was found that the NE of unconfined metastatic melanoma cells blebs and ruptures more frequently at structurally vulnerable sites as a result of high Rho-ROCK1/2-driven actomyosin contractility compared to unconfined primary melanoma cells or melanocytes and transcriptomic analyses showed an upregulation of NE genes. TOR1AIP1 was selected because it was found to be upregulated in metastatic melanoma and its encoded protein, the inner nuclear membrane (INM) protein lamina-associated polypeptide (LAP)1, was confirmed to be overexpressed at the edge of primary melanoma tumours and metastases. Third, it was discovered that LAP1 supports NE blebbing, constrained migration and invasion in an isoform-specific fashion. LAP1B has a longer amino terminus (NT) than LAP1C and it was shown to bind more strongly to nuclear lamins and to be less mobile. While LAP1C promotes NE blebbing, constrained migration and invasion, the strong nucleoplasmic tethering provided by LAP1B and LAP1B-mediated activation of Torsin-1A are inhibitory. Overall, this work demonstrates that nucleo-cytoskeletal rearrangements in metastatic melanoma cells ultimately impact NE dynamics and feed into an aggressive amoeboid cancer cell state. These findings provide a better understanding of the molecular players that orchestrate NE dynamics during tumour cell migration and point LAP1 as an interesting candidate with unprecedented functions of broad translational relevance.
Date of Award1 Sept 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorVicky Sanz Moreno (Supervisor) & Jeremy Carlton (Supervisor)

Cite this