Lamin B Receptor Upregulation in Metastatic Melanoma Causes Cholesterol-Mediated Nuclear Envelope Fragility

Metastatic cancer cells migrate through regions of tissue confinement, causing nuclear envelope (NE) rupture and heritable DNA damage. We discovered that cells from multiple cancers have increased NE fragility in confinement and transcriptional upregulation of nuclear genes compared to benign counterparts. A bioinformatic-driven siRNA screen revealed that lamin B receptor (LBR) upregulation correlates with melanoma progression and NE fragility. Increased LBR cholesterol synthase activity causes accumulation of cholesterol in the NE, which is necessary and sufficient for nuclear deformability and NE rupture in cells confined in vitro and is associated with NE rupture in invasive cells migrating out of tumor organoids and tumors in vivo. Thus, LBR upregulation causes excess NE cholesterol, driving nuclear fragility in confined migrating melanoma cells, establishing a direct role for nuclear membrane lipid composition in metastatic cancers.