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Some of the most deadly skin cancers may start in stem cells that lend color to hair and originate in hair follicles rather than in skin layers, a new study finds.

Hair follicles are complex organs that reside within skin layers. It is there that immature pigment-making cells develop cancer-causing genetic changes and—in a second step—are exposed to normal hair growth signals, say the study authors.

Past models of the disease had argued that sunlight (e.g., ultraviolet radiation) was a major risk factor for melanoma, but current work argues that the triggers are always there in normal follicles.

The new study, , found that unlike their normal counterparts, newly cancerous pigment stem cells then migrate up and out of the follicles to establish melanomas in nearby surface skin before spreading deeper. The study was conducted in genetically engineered mice, with the results confirmed in human tissue samples.

“By confirming that oncogenic pigment cells in hair follicles are a bona fide source of melanoma, we have a better understanding of this cancer’s biology and new ideas about how to counter it,” says corresponding study author , associate professor in the at �ٺ���Ƶ and a member of the at Perlmutter Cancer Center.

Invisible Trail Revealed

The study results reflect development, in which a human starts as a single stem cell, the embryo, and becomes a fetus made up of hundreds of cell types. Along the way, stem cells divide, multiply, and specialize, until—finally—they become cells capable of playing a single role (e.g., nerves or skin).

Complicating matters, stem cells can become more than one cell type and can shift between them. This flexibility is useful during development, but can be dangerous in adults, in whom cancer cells are thought to reacquire aspects of early embryonic cells. Because of this malleability, researchers have theorized that melanomas might arise from several stem cell types, making them hard to treat and their origins difficult to track.

The new study addresses the stem cells that mature into melanocytes, cells that make the protein pigment melanin, which protects skin by absorbing some of the sun’s ultraviolet, DNA-damaging rays. By absorbing some wavelengths of visible light, but reflecting others, pigments “create” hair color.

In a series of elegant steps, the research team established a new mouse model for the study of melanoma, one engineered such that the team could edit genes in follicular melanocyte stem cells only (the c-Kit-CreER mouse). This capability enabled researchers to introduce genetic changes that made only melanocyte stem cells—and their descendants destined to form melanomas—glow no matter where they travelled.

Able to accurately track a key stem cell type for the first time, the authors confirmed that melanoma cells can arise from melanocyte stem cells, which abnormally migrate up and out of hair follicles to enter the epidermis, the outermost layer of skin. The team tracked the same cells as they multiplied there and then moved deeper into the skin layer called the dermis.

Once there, the cells shed the markers and pigment that went with their follicular origins, presumably in response to local signals. They also acquired signatures similar to nerve cells (neurons) and skin cells (mesenchymal), molecular characteristics “almost exactly like” those noted in examinations of human melanoma tissue.

Knowing where to look for the original, cancer-causing event, the researchers temporarily eliminated signals one by one in the follicular environment to see whether cancer still formed in their absences. In this way, the team confirmed that follicular melanocyte stem cells, even though they had cancer-causing genetic mutations, did not multiply or migrate to cause melanomas unless also exposed to endothelin (EDN) and WNT. These signaling proteins normally cause hairs to become longer and pigment cells to multiply in follicles.

“Our mouse model is the first to demonstrate that follicular oncogenic melanocyte stem cells can establish melanomas, which promises to make it useful in identifying new diagnostics and treatments for melanoma,” says first study author Qi Sun, PhD, a postdoctoral fellow in Dr. Ito Suzuki’s lab. “While our findings will require confirmation in further human testing, they argue that melanoma can arise in pigment stem cells originating both in follicles and in skin layers, such that some melanomas have multiple stem cells of origin.”

Along with Dr. Ito Suzuki and Dr. Sun, study authors from the Departments of Dermatology, , and at �ٺ���Ƶ were Wendy Lee; Makoto Takeo; Chae Ho Lim; ; ; and Rana Moubarak, PhD.

Also study authors were Yasuaki Mohri and Emi Nishimura in the Department of Stem Cell Biology at Tokyo Medical and Dental University; Xiaowei Xu in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania; Peggy Myung in the Department of Dermatology at Yale Cancer Center; Radhika Atitin the Department of Biology at Case Western Reserve University in Cleveland; Mark Taketo of the Graduate School of Medicine at Kyoto University; Denise Gay of the Institut de biologie François Jacob in Fontenay-aux-Roses, France; and Dieter Saur of the German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and Technische Universität München.

The work was funded by National Institutes of Health grants P30CA016087, R01 AR059768, R01 AR066022, R21 ES023034, and P50CA016087, along with NYSTEM institutional training grant C026880. Additional funding for the study was provided by the Arnold and Mabel Beckman Foundation and the American Skin Association.

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