# Lamin B receptor upregulation in metastatic melanoma causes nuclear envelope fragility in confined migration during cancer invasion

## TL;DR

This study shows that increased LBR protein in melanoma makes the nucleus fragile, leading to DNA damage and cancer spread.

## Contribution

The study identifies LBR as a novel driver of nuclear envelope fragility in metastatic melanoma.

## Key findings

- LBR overexpression increases nuclear deformability and fragility in melanoma cells.
- LBR-induced nuclear ruptures correlate with increased metastasis and reduced patient survival.
- LBR's sterol reductase activity is essential for nuclear envelope instability in confined environments.

## Abstract

To metastasize, cancer cells migrate from the primary tumor through dense tissues to spread to distant organs. During this journey, as cells squeeze through thin passages in tissues, the membrane surrounding the cancer cell’s nucleus can burst, causing DNA damage and mutations, making it more malignant. We found that a specific protein, lamin B receptor (LBR), gets overproduced in aggressive melanoma. We found in isolated cancer cells that excess LBR causes cell nuclei to become more deformable and fragile, making them susceptible to rupture and that LBR-induced nuclear fragility happens in skin tumors in mice, increases cancer spreading, and correlates with decreased melanoma patient survival. This identifies LBR as a potential therapeutic target in the prevention of melanoma metastasis.

Cancer cells migrate through regions of tissue confinement during metastasis, causing nuclear envelope (NE) rupture, which generates heritable DNA damage and disease aggression. We sought to determine if NE rupture was intrinsic to malignant transformation and seek a mechanistic cause. We found that metastatic cells from multiple cancer subtypes have increased NE fragility in confinement compared to their benign counterparts. Meta-analysis of transcriptomic data from clinical samples of melanoma progression together with an siRNA-based live-cell confinement screen revealed that lamin B receptor (LBR) transcriptional upregulation correlates with melanoma progression and NE fragility. LBR is an inner nuclear membrane protein (INM) that scaffolds lamins and chromatin and has sterol reductase activity in the cholesterol biosynthesis pathway. Applying superresolution and atomic force microscopies to characterize the cellular and biophysical events leading to NE rupture revealed that upregulated LBR increased nuclear deformability and can generate local ruptures of the INM, promoting blebs in the nuclear membrane that burst to release nuclear contents into the cytoplasm. Structure–function analysis showed that LBR’s sterol reductase activity is required for its promotion of NE fragility in cells confined in vitro. Use of tumor organoids and an in vivo melanoma model revealed that upregulation of LBR was associated with increased NE fragility, metastatic invasion, and decreased patient survival. Thus, upregulation of LBR in melanoma promotes nuclear deformability, while LBR’s sterol reductase activity causes fragility and instability of the nuclear membrane, and these changes in the nucleus provide a possible mechanism for increased genetic heterogeneity in melanomas.