A molecular seesaw drives healthy skin development, Stanford Medicine researchers find

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Keratinocytes, shown in red, are more prevalent on the surface of lab-grown human skin organoids when the NEDD8 pathway is blocked (center) as compared with control (left). Too few keratinocytes are present when the SUMO2 pathway is blocked (right).

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Skin Cancers June 25, 2026

A molecular seesaw drives healthy skin development, Stanford Medicine researchers find

By Krista Conger

Two opposing biological pathways balance stem cell maintenance with skin development; topical drug treatments targeting them may treat skin cancers and disorders.

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Two proteins with opposing functions orchestrate the development and maintenance of healthy skin, Stanford Medicine researchers have found. Modulating their activity with topical drugs could reduce inflammation, aid wound healing, and slow or halt the growth of skin cancer, the researchers believe.<br>\nThe proteins are part of a family called ubiquitin-like proteins. Ubiquitination controls the targeted destruction and disposal of unneeded proteins in a cell. But in the skin, certain ubiquitin-like proteins instead switch on or off wide swaths of genes involved in cellular growth and development, the study found. In particular, they trigger progenitor, or stem, cells in the lower layer of the skin to either mature and migrate to the skin surface or to self-renew.<br>\n“These two ubiquitin-like protein systems are remarkably dedicated and opposite in their functions,” said Paul Khavari, MD, PhD, chair of dermatology at the Stanford School of Medicine and senior author of the study. “One promotes the stem-cell state while the other drives differentiation. It’s like having two opposing forces that determine a cell’s fate.”<br>\nKhavari, who is the Carl J. Herzog Professor in Dermatology in the School of Medicine, chief of dermatology at Veterans Affairs Palo Alto and a member of the Stanford Cancer Institute, is the senior author of the study, which was published June 25 in Science. Clinical instructor of dermatology Mårten Winge, MD, PhD, and MD/PhD student Leandra Jackrazi are the lead authors of the study.<br>\n“What’s really exciting is how specific these effects are,” Winge said. “When we manipulate one system or the other, we see very clear and opposite outcomes. This specificity is unusual for ubiquitin-like pathways and makes these systems particularly attractive for therapeutic targeting.”<br>\nThink of the outer layer of your skin as two distinct compartments. On the lower level, progenitor, or skin-specific stem cells, bide their time, waiting to transform into more specialized cells called keratinocytes. Keratinocytes form the critical skin barrier that keeps moisture in (and out!), excludes infection-causing pathogens, repels DNA-damaging ultraviolet rays and harbors the myriad nerve endings that allow us to sense our surroundings.<br>\nCloistered in their basement-level green room, the progenitor cells divide just enough to keep their numbers robust. But when needed — after injury or infection or when skin cells naturally slough off — a subset of progenitor cells undergo a process known as differentiation, during which they acquire the specialized traits necessary to face the world while migrating to the skin’s surface. Disruptions in this delicate balance between stem cell maintenance and their maturation into adult keratinocytes can lead to psoriasis, poor wound healing and skin cancer.<br>\nThe differentiation switch<br>\nThe researchers were interested in understanding how the differentiation switch is flipped. They used a wide swath of experimental approaches to assess dynamic changes in the expression of thousands of genes and proteins at various stages of keratinocyte differentiation. They found that the maturing cells expressed increasing levels of genes and proteins involved in skin formation and decreasing levels of others associated with stem cell maintenance. Many of the proteins that decreased during differentiation bore small molecular tags that identify locations recognized by other proteins in the ubiquitin pathways — giving a hint that ubiquitination may be involved in the differentiation switch the researchers were seeking.<br>\nDisrupting the expression of more than 200 genes in the ubiquitin pathway during keratinocyte maturation highlighted two subpathways essential for proper differentiation: NEDDylation and SUMOylation. Hobbling the NEDDylation pathway supercharged differentiation, while blocking SUMOylation prevented differentiation. Similar results were obtained when the pathways were blocked pharmacologically with existing drugs in both human keratinocytes grown in the laboratory and in human skin organoids —...