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

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. LBR acts as both a nuclear scaffold for lamins and chromatin and a sterol reductase, a rate-limiting enzyme in cholesterol synthesis. Analysis of LBR using human disease mutations in metastatic melanoma cells revealed that LBR sterol reductase activity is required for NE fragility in cells confined in vitro. Utilizing the membrane tension sensor Flipper and the lipid packing dye laurdan we find upregulation of LBR causes increased cholesterol partitioning in the NE, locally decreasing membrane tension, promoting rupture. Analysis of invasive cells migrating out of tumor organoids in vitro and skin tumors in vivo revealed upregulation of LBR was associated with increased NE rupture during metastasis. Thus, LBR upregulation in melanoma causes cholesterol-mediated NE fragility during metastasis, establishing a direct role for nuclear membrane lipid composition in NE integrity of metastatic cancers.