Abstract A006: the NALCN Channel Regulates Metastasis and Non-Malignant Cell Dissemination

We identify the Sodium Leak Channel Non-Selective Protein (NALCN) as a key regulator of cancer metastasis and non-malignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric (Prom1CreERT2/LacZ;KrasG12D;Trp53Flx/Flx; n=269), intestinal (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=141) or pancreatic adenocarcinomas (Pdx1-Cre;KrasG12D;Trp53Flx/+; n=55) in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=28) with gadolinium–an imaging contrast agent and NALCN channel blocker–similarly increased CTCs and metastasis. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer(Prom1CreERT2/LacZ; n=174), 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 anti-metastatic therapies. Citation Format: Eric Rahrmann, David Shorthouse, Amir Jassim, Linda Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory Hannon, Radhika Iyer, Jay Blundon, Filipe Lourenço, Jonathan Kay, Rosaylnn Nazarian, Benjamin Hall, Stanislav Zakharenko, Douglas Winton, Liqin Zhu, Richard Gilbertson. The NALCN channel regulates metastasis and non-malignant cell dissemination [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A006.