Melanoma Cells Metastasize When Key Calcium Entry Pathway is Suppressed, Study Shows

PHILADELPHIA (September 27, 2022)—Researchers at Fox Chase Cancer Center have identified a new cellular pathway that plays a key role in causing melanoma to become invasive and hastening its spread.

Specifically, their study, which was published recently, shows how a system that mediates the entry of calcium into cells can be suppressed to promote metastasis, the spread of cancer cells from the place where they first formed to another part of the body. This was very surprising, since there have been other studies showing that boosting calcium signals causes metastasis.

“We’re showing that modest suppression of calcium signals has its own effect. We describe it as a ‘Goldilocks effect,’ where promoting calcium signals may very well be pro-metastatic and blocking calcium signals may very well block metastasis, but modestly weakened calcium signals make the cells go a little crazy,” said Jonathan Soboloff, PhD, a professor in the Blood Cell Development and Function research program at Fox Chase.

“Contrary to previous understanding, the relationship between calcium and cancer is not linear, but rather depends on context,” said Scott Gross, PhD, the first author of the study and a recent graduate of the Soboloff group, who is now a research scientist at Eliksa Therapeutics. “This has implications not only for melanoma but, potentially, many other malignancies.”

The team focused on a process called store-operated calcium entry, or SOCE, which senses when intracellular calcium stores are low and signals the cell to open calcium channels to refill these stores. They found that exposing melanoma cells to UV radiation triggered cholesterol biosynthesis, which in turn suppressed SOCE, causing the melanoma cells to metastasize.

They also found that suppressing SOCE with drugs alone produced the same result, indicating that it’s the calcium entry pathway itself that drives metastasis and that UV radiation isn’t required for the process to take place. Restoring normal SOCE function prevented metastasis.

Further analysis found that suppressing the uptake of calcium led to metabolic changes and the formation of glycoproteins, proteins with sugars attached to them which are already known to promote metastatic cancer growth.

Researchers demonstrated the effect in lab and mouse models and also repeated their results in human melanoma cells freshly isolated from patients. The findings could contribute to ongoing research looking at the potential of statin drugs, which are used to lower cholesterol, to block melanoma metastasis.

“We’re not the first people to talk about statins in melanoma, but we’re providing a mechanism for why statins might be having this effect. Statins block cholesterol levels, and we’re showing cholesterol as an integral piece in the middle of this process,” said Soboloff, who is also a professor in the Department of Cancer and Cellular Biology and the Fels Cancer Institute for Personalized Medicine at the Lewis Katz School of Medicine at Temple University.

Soboloff said that melanoma forms in the basal layer of the skin, a low-calcium environment, but that when it metastasizes it must enter other parts of the body where calcium levels are higher. That could explain why decreasing the activity of calcium channels would be advantageous for melanoma cells. It could also suggest that other types of cancer might not respond to SOCE suppression in the same way, he noted.

As a follow-up, researchers hope to determine which glycoproteins are formed when SOCE is disrupted. They also want to zero in on the immediate changes that happen in a melanoma cell after UV exposure.

“This paper focuses on events that happen weeks after exposure,” Soboloff said. “We’d like to know what happens right away and what the early events are that lead to these longer-term changes.”

The paper, “Suppression of Ca2 Signaling Enhances Melanoma Progression,” was published in The EMBO Journal.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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