Melanoma Cells’ Skin Neighbors Can Stoke Tumor Expansion, Study Shows

Melanoma Cells’ Skin Neighbors Can Stoke Tumor Expansion, Study Shows

A type of skin cell that is interspersed with the skin cells from which malignant melanoma arises can promote melanoma tumor expansion, a study says.

Melanoma-related skin cells are called melanocytes, and the cells with which they are interspersed keratinocytes. Researchers discovered that the loss of a molecule in keratinocytes can lead to abnormal contacts with melanocytes, stoking melanoma growth.

The study, “The epidermal polarity protein Par3 is a non–cell autonomous suppressor of malignant melanoma,” indicated that analyzing healthy tissue surrounding a tumor can help scientists better understand disease processes. The report was published in the Journal of Experimental Medicine.

“So far, melanoma research has mostly concentrated on intrinsic changes of the tumor cell or on its recognition by the immune system,” Sandra Iden, senior study author, said in a press release.

Even though malignant melanoma is a tumor arising in melanocytes — the skin cells that cause people to tan when exposed to ultraviolet light — the cells are dispersed with keratinocytes.

This proximity led researchers at the Cluster of Excellence on Aging Research (CECAD) at the University of Cologne in Germany to suspect that processes in keratinocytes could contribute to melanoma formation.

To try to understand these processes, the team experimented with cell signaling factors in mice and analyzed tissue samples from skin cancer patients, collected at different stages of melanoma development.

They discovered that keratinocytes work to prevent melanoma formation through factors known as polarity proteins. Such proteins, particularly one called Par3, control cell shape and function, making sure that the part of the cell facing the outside of the skin is different from its inside.

When the protein was lost in the mice keratinocytes, there was an increase in a protein called P-cadherin, which is crucial for connections between cells.

“We were able to specifically interfere with polarity protein signaling in epithelial cells, surrounding the tumor. We found that this disrupts the direct communication between keratinocytes and melanocytes, which resulted in increased tumor formation and metastasis,” Iden said.

When P-cadherin increased, melanocytes and keratinocytes bound stronger to each other, prompting tumor cells to expand.

Analysis of patient tissue confirmed what researchers found in mice: The more a tumor advanced, the less Par3 was present in neighboring keratinocytes. Just as in the mice, the loss of Par3 gave rise to more P-cadherin.

Researchers also found that patients with higher levels of P-cadherin had a lower survival rate than those with lower levels.

“We can now show that the surrounding epithelium has a strong impact on melanocyte fate and early stages of tumor formation. Keratinocytes keep the melanocytes in check and thereby decrease the risk of developing a melanoma,” Iden said.

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