Highlights in Cancer Research: May 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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7. The NALCN channel regulates metastasis and nonmalignant cell dissemination

Rahrmann, E., P. et al. Nat Genet. 54: 1827–1838. (2022).
doi: 10.1038/s41588-022-01182-0.

Summary of the findings

Metastasis, the process by which cancer cells spread through the body, is the leading cause of cancer-related death. Despite decades of study, this process remains poorly understood and resistant to treatment. Metastasis has historically been assumed to be an abnormal process mediated by primary cancers. However, by using mouse models of gastric, intestinal and pancreatic cancer, we have divorced metastasis from upstream tumorigenesis and linked it to a natural physiologic process, which is central to the maintenance of normal tissues, uncovering a new paradigm for metastasis. We identified that genetic deletion or pharmacological blockade (GdCl3) of the Sodium Leak Channel Non-Selective Protein (NALCN) significantly increased epithelial cell dissemination into the blood from both normal and malignant tissues revealing this cascade as a cancer-independent phenomenon and a novel treatment target. NALCN loss- of-function in tumour-bearing mice significantly increased circulating tumour cell numbers in the peripheral blood and seeded metastases body-wide. In non-tumour-bearing animals, disseminated epithelial cells did not cause metastases but seeded in organs and apparently contributed to the normal structures of the organs such as renal tubules and glomeruli. These findings will allow refinement of the current model of metastasis and have unmasked a potential novel target for anti-metastatic therapies.

We have identified a single ion channel, NALCN, as a key regulator of cancer metastasis and non-malignant cell dissemination.

Future impact

Current chemotherapy and radiation fail to cure many cancer patients and tumours often relapse in a morphologically more aggressive and metastatic state, the primary cause of cancer-related deaths. Developing anti-metastatic therapies has proven difficult since potential therapeutic targets in primary tumours that drive metastases e.g., mutant oncoproteins, have proved hard to find. By divorcing the process of metastasis from oncogenic transformation we have uncovered a natural cell dissemination phenomenon that holds promise as a new target for anti- metastatic therapies.