A breakthrough in metastasis could lead to better cancer treatments

Understanding how metastasis works.
Deniz Yildiran
Leukemia stock image.
Leukemia stock image.

Chawalit Banpot/iStock 

In the universal fight against cancer, metastasis is one of the most unpleasant factors that could make matters even worse; and there is still much to comprehend in the spread process. Cambridge scientists might have unveiled a breakthrough in understanding how metastasis works.

A team of scientists at the Cancer Research UK Cambridge Institute and the University of Cambridge has discovered that blocking a particular protein's activity kicked off metastasis in mice with cancer.

The research has been published in the journal Nature Genetics.

Scientists also found that metastasis is not a process only cancer can cause. When they removed the NALCN protein from mice without cancer, they realized that healthy cells also left their original tissue and took a trip around the body to join other organs.

In an experiment, healthy cells of the pancreas traveled to the kidney and transformed into healthy kidney cells, which indicates that metastasis is not an abnormal process pertaining to cancer only. Until now, it has been thought so by the scientific community.

It seems that our organs are part of a collaborating machine.

NALCN and metastasis

"These findings are among the most important to have come out of my lab for three decades," said Professor Richard Gilbertson, group leader for the study and Director of the CRUK Cambridge Centre.

"Not only have we identified one of the elusive drivers of metastasis, but we have also turned a commonly held understanding of this on its head, showing how cancer hijacks processes in healthy cells for its own gains. If validated through further research, this could have far-reaching implications for how we prevent cancer from spreading and allow us to manipulate this process to repair damaged organs."

NALCN stands for sodium (Na+) leak channel, non-selective. Sodium leak channels are mainly expressed in the central nervous system. However, they can also be found in different internal parts of the body.

These channels are placed over the cell membranes, which control the movement of sodium ions into the cell. However, scientists haven't been able to figure out what exactly the channels have to do with the spread of cancer.

"We are incredibly excited to have identified a single protein that regulates not only how cancer spreads through the body, independent of tumor growth, but also normal tissue cell shedding and repair," said Dr. Eric Rahrmann, lead researcher of the study.

"We are developing a clearer picture of the processes that govern how cancer cells spread. We can now consider whether there are likely existing drugs which could be repurposed to prevent this mechanism from triggering cancer spreading in patients."

"Once cancer has spread from the first tumor, it is harder to treat because we are looking at multiple sites in the body and working with new tumors that may be resistant to treatment. Discovering that a cancer has spread is always devastating news for patients and their families, and so we are delighted to have supported this incredible research which may one day allow us to prevent metastasis and turn cancer into a much more survivable disease," Director of Research at CRUK, Dr. Catherine Elliott, said.

Abstract:

We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant 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 tumor incidence, but markedly increased the number of circulating tumor 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 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 antimetastatic therapies.

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