Researchers at the Hebrew University of Jerusalem have uncovered a key biological mechanism that acts as a primary defense against the progression of aggressive skin cancers, offering new insights into patient risk and potential therapeutic strategies.

The study, conducted at the Lautenberg Center for Immunology and Cancer Research within the university’s Faculty of Medicine, focused on cutaneous squamous cell carcinoma (cSCC), the second most common form of skin cancer worldwide. While many cases are treatable, a subset can become highly aggressive, spreading to distant organs and resisting conventional therapies.

Led by PhD student Tirza Bidany-Mizrahi under the supervision of Rami I. Aqeilan, and in collaboration with scientists from the University of Rome, the research identifies the protein WWOX as a critical “guardian” of skin cell identity.

Published in Proceedings of the National Academy of Sciences (PNAS), the study demonstrates that WWOX (WW domain-containing oxidoreductase) maintains the stability and function of skin cells by supporting another key protein, p63—a master regulator that preserves epithelial structure.

Using advanced genetic models and human tissue samples, the researchers found that loss of WWOX leads to a sharp decline in p63 levels. This triggers a process known as epithelial-to-mesenchymal transition (EMT), in which cancer cells lose their epithelial characteristics and gain the ability to migrate and invade other tissues, including the lungs.

The study further shows that WWOX loss significantly accelerates cancer progression. In models lacking both WWOX and the tumor suppressor p53, tumors developed earlier and were markedly more aggressive and poorly differentiated. Notably, all subjects in this double-deficiency group developed tumors, compared to significantly lower rates in control groups.

The full study, titled “WWOX Maintains Epidermal Identity and Suppresses EMT to Prevent Aggressive Cutaneous Squamous Cell Carcinoma,” is available via PNAS.