Metastasis Is Not A Cancer Phenomenon
Ninety-percent of cancer deaths are a result of metastasis. This process, by which cancer cells spread from the primary tumour to other organs in the body, remains shrouded in mystery.
Metastasis is poorly understood, even though it has been studied extensively over several decades. It is regarded as an abnormal process, mediated by primary cancers, that is resistant to treatment. However, our work has, for the first time, divorced metastasis from upstream tumorigenesis, uncovering a completely new paradigm for metastasis. Specifically, we found that the Sodium Leak Channel Non-Selective Protein (NALCN) regulates epithelial cell trafficking into the blood from both normal and malignant tissues unmasking this cascade as a cancer-independent phenomenon and a novel treatment target (Rahrmann EP et al., Nature Genetics, in press).
The NALCN channel regulates cell dissemination
Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric, lung, prostate, head & neck, and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumour incidence. Instead, it markedly increased metastasis and the number of circulating tumour cells (CTCs) in the blood of these mice. CTCs passage from the primary tumours to form metastasis somewhere else in the body. Treatment of mice with gadolinium (GdCl3)–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, caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumour-bearing animals. These cells travel to distant organs to form typical structures, including lung epithelium, kidney glomeruli, and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer status, suggesting a degree of separation between the initial stages of metastasis and tumourigenesis. In our view, the findings of this study will improve the current model of metastasis and have unmasked a potential novel target for anti-metastatic therapies.