Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit

Abstract

The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression.

DOI: http://dx.doi.org/10.7554/eLife.14277.001

eLife digest

Cancer can develop when cells in the body gain mutations that allow them to grow and divide rapidly. Some of these mutations may affect the activity of genes that usually act to prevent cancer from developing. Several such “tumor suppressor” genes have been identified, but it is likely that many remain undiscovered and it is far from fully understoodhow all these genes work. One way to identify new tumor suppressor genes is to examine tumors to search for genes that have gained mutations that block their activity, known as loss-of-function mutations.

Hatzold et al. identified a new and rather unexpected tumor suppressor gene by studying a zebrafish mutant that develops skin cancer as the embryo grows. The experiments showed that cells in the skin of the developing embryos of this mutant grow excessively and start to invade deeper tissues in the body. This behavior is caused by loss-of-function mutations in a gene called atp1b1a. This gene encodes part of an ion pump protein that helps to control the amount of water and ions in cells and in body fluids.

Further experiments showed that this tumor suppressor gene does not act in the skin cells themselves but in other cells of organs such as the kidney. The kidney is involved in controlling the water and ion content of the body (known as osmoregulation), and the atp1b1a mutants have lower levels of ions and increased levels of water than normal zebrafish. Cancer formation could be completely blocked when the mutant embryos were kept in a solution that had the same salt and water content as the animals, instead of regular fresh water. This suggests that exposure of cells to body fluids with decreased ion and increased salt contents, a condition also called hypotonic stress, increases the risk of developing some tumors.

Osmoregulatory organs that are not working efficiently, or injuries that expose cells to different ion and water levels can both cause hypotonic stress. The next steps are to investigate whether this stress also promotes cancer formation in mammals, including humans.

DOI: http://dx.doi.org/10.7554/eLife.14277.002