Journal Article

The NALCN channel regulates metastasis and nonmalignant cell dissemination

Rahrmann, Eric P., Hannon, Gregory J., Blundon, Jay A., Fatemi, Atefeh, Hall, Benjamin A., Hu, Linda P., Vogel, Peter, Zakharenko, Stanislav S., Zhu, Liqin, Ortiz, Mariaestela, Lourenço, Filipe C., Gilbertson, Richard J., Winton, Douglas J., Shorthouse, David, Jassim, Amir, Paez-Ribes, Marta, Kay, Jonathan, Iyer, Radhika, Nazarian, Rosalynn M., Mahler-Araujo, Betania

2022

Overview

We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice with gadolinium—a NALCN channel blocker—similarly increased CTCs and metastases. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium, and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for antimetastatic therapies. The ion channel NALCN regulates cell shedding in mice and enhances metastasis in mouse models of cancer. Disseminated cells without oncogenic mutations form normal structures at secondary sites, suggesting that cell shedding is a physiological process that is hijacked during tumorigenesis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/249/2510 / 631/67/322 / Agriculture / Animal Genetics and Genomics / Animal models / Animals / Biomedical and Life Sciences / Biomedicine / Blood levels / Cancer / Cancer Research / Cell culture / Cell growth / Colorectal cancer / Deletion / Epithelial cells / Epithelium / Gadolinium / Gene deletion / Gene Function / Genes / Glomerulus / Histology / Human Genetics / Humans / Ion channels / Ion Channels - genetics / Kidneys / Membrane Proteins - genetics / Metastases / Metastasis / Mice / Morphology / Mutation / Neoplasms / Pancreatic cancer / Prostate / Shedding / Small intestine / Stem cells / Tubules / Tumor cells / Tumorigenesis / Tumors