Researchers have long known that the developmental regulator WNT5A plays a role in the dissemination of tumor cells.

Now, investigators from Johns Hopkins University have discovered that its suppression plays a role in the growth of metastases after a period of dormancy as well.

The work gives new insights into the role of the aging microenvironment in melanoma relapse.

Melanoma is among the tumor types where relapse can occur decades after the original tumor. "You can have someone diagnosed in their 40s with a melanoma and at 65 they present with a bunch of metastases," Ashani Weeraratna told BioWorld Science. "The most obvious thing that happens in this time is that you age."

Weeraratna is the E.V. McCollum Professor and chair of the department of biochemistry and molecular biology at the Johns Hopkins University's Bloomberg School of Public Health, and a Bloomberg Distinguished Professor (cancer biology), professor of oncology, and co-leader of the cancer invasion and metastasis program at the Kimmel Cancer Center.

She is also the senior author of the paper reporting the findings, which was published in the June 1, 2022, issue of Nature.

Weeraratna and her colleagues were interested in age-related changes in the microenvironment that could explain why tumor cells might suddenly start growing years after they originally disseminated.

While part of the reason is that the immune system declines with age, making it easier for metastases to escape immune surveillance. But there is also evidence for active processes that make it easier for metastases to grow.

"We wanted to know what the TME [was] secreting that woke these cells up," Weeraratna said.

The team first implanted melanoma cells into young and aged mice, respectively, and looked at both the growth of tumors within the skin, and metastases in the lungs. They found that in the skin, tumors grew more slowly in older animals. Cells traveled to the lungs in both young and aged animals. But while in the young animals, single cells remained in the lungs without growing, in older animals those cells seeded metastases.

Proteomic analyses comparing the lung fibroblasts from individuals younger than 35 to those older than 55 showed that one of the biggest differences was in the level of secreted frizzled related protein 1(sFRP1), which antagonizes Wnt.

"Mitch's" – first author Mitchell Fane's "work started to show that the signaling within the distal environment had to shut off WNT5A -- that was fascinating to us," Weeraratna said.

The difference in lung metastases between young and aged animals "was dramatic, but not unexpected," she added. "What was unexpected to me was the role of WNT5A."

The findings give deeper insight into the role of WNT5A in melanoma.

"What we saw was a real dichotomy between growth and invasion," Weeraratna said. Melanoma can switch between those two states, and the work now published in Nature showed that "these cells use different arms of the WNT pathway to switch back and forth between these two states... When the WNT5A signaling pathway is activated, the cells are highly invasive but ... don't grow fast. By contrast, when the WNT5A signaling pathway is suppressed, the cells grow much faster."

Translationally, the work is as much a cautionary tale as anything else for now. Weeraratna said it might be possible to target an upstream signaling node called porcupine to prevent both growth and dissemination. But "every time we target WNT5A, the tumor cells grow much faster."