The NALCN channel regulates metastasis and non-malignant cell dissemination (scRNA-Seq)

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, intestinal or pancreatic adenocarcinomas in mice did not alter tumour incidence, but markedly increased the number of circulating tumour 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 tumour-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 tumourigenesis and unmasking a potential new target for anti-metastatic therapies. Single cell RNAseq from normal tissues (kidney, lung, liver, epididymis, uterus, stomach), tumours (small intestine, gastric), metastases, circulating ZSG+ cells from tumour and non-tumour bearing animals, PBMCs