New research shows that melanoma's transition to an invasive and subsequently metastatic disease is triggered by direct contact between melanoma cells and differentiated keratinocytes in the epidermis, which in turn sparks Notch signaling. Understanding the molecular events that occur early on in this disease may enable the development of therapeutic strategies to keep its aggression at bay.

In its earliest stage, melanoma proliferates within a basal skin layer that separates the outer epidermis and inner dermis, but the disease is in situ, meaning melanoma cells aren't yet invasive or metastatic. What provokes their aggression hasn't been well understood; however, a recent study suggests that the surrounding microenvironment, along with Notch signaling, may be key (Mol Cell 2015;59:664–76).

“To metastasize, melanoma cells need to invade the dermis, which contains blood vessels,” explains senior author Carmit Levy, PhD, an investigator at Tel Aviv University's Sackler School of Medicine in Israel. “Oddly, before heading deeper [into the dermis], they first extend upward, to the top of the epidermis. I wondered why they were apparently starting out in the wrong direction, and it occurred to me that our skin's outermost layer might contain the trigger for invasion.”

Levy and her group explored their hunch by co-culturing noninvasive melanoma cells with different types of normal human skin cells, including differentiated and basal keratinocytes from the epidermis. Only melanoma cells interacting with differentiated keratinocytes became highly invasive—measured via a gel-based infiltration assay—and displayed reduced pigmentation, another marker of invasive capability. Mice treated with this combination of melanoma cells and differentiated keratinocytes also had significant numbers of lung metastases.

Aware that melanoma cells express the Notch receptor, and that one of its ligands, DLL1, is expressed in differentiated keratinocytes, the researchers were not surprised to observe significant Notch activity when both cell types were co-cultured. Analyses of patient samples showed that melanoma cells far from DLL1-expressing differentiated keratinocytes remained noninvasive; on the other hand, direct contact between these cells induced Notch signaling and dermal invasion.

“Melanoma cells have to reach a particular microenvironment within the epidermis where Notch ligand–expressing cells reside,” Levy says. “Once contact is made, it triggers an entire cascade of events, leading to metastasis.”

Next, the researchers investigated this cascade in greater molecular detail. They found that in noninvasive melanoma cells, the proteins MITF and RBPJK cooperatively bind to and repress miR-222/221, two microRNAs in close proximity to each other. The Notch receptor's intracellular domain—cleaved when direct interaction of melanoma cells with differentiated keratinocytes activates Notch signaling—interferes with this repression by removing MITF; subsequently, miR-222/221 is activated and precipitates melanoma cells' ability to invade the dermis.

“This [study] sheds significant light on the complex relationships between malignant and nonmalignant cells in tumor microenvironments,” says Marc Ernstoff, MD, director of the melanoma program at Cleveland Clinic's Taussig Cancer Institute, OH. “Understanding the pathways by which melanoma turns invasive, and how normal cells nearby contribute, will allow us to develop therapeutic strategies that can change the biological behavior of primary tumors.”

For instance, Levy envisions delivering Notch inhibitors directly to the epidermis—perhaps via a skin cream. Then “patients with atypical moles could receive anti-Notch treatment, even while being monitored,” she says.

“Melanoma's gestation is a lengthy one,” Levy adds, “and as we uncover more of this disease's early events, we may someday be able to prevent metastasis altogether.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2015 American Association for Cancer Research.
2015