Skin Cancer Study Identifies WWOX Protein as Key Regulator of Tumor Progression
Researchers show that loss of WWOX disrupts p63 stability, driving tumor invasion and identifying potential biomarkers for aggressive disease
Jerusalem, April 16, 2026 (GLOBE NEWSWIRE) — Researchers have identified a molecular mechanism that helps prevent common skin cancers from becoming aggressive and metastatic. The study, published in Proceedings of the National Academy of Sciences (PNAS), shows that loss of the protein WWOX enables tumor cells to transition into a more invasive and treatment-resistant state.
The research was led by PhD student Tirza Bidany-Mizrahi under the supervision of Prof. Rami I. Aqeilan at the Faculty of Medicine of the Hebrew University of Jerusalem, in collaboration with Dr. Mara Mancini, Prof. Gerry Melino, and Prof. Eleonora Candi from the University of Rome.
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer worldwide. While many cases are successfully treated, a subset of tumors progresses into aggressive disease that can spread to other organs and become resistant to standard therapies. The new findings provide insight into the biological mechanisms that drive this progression and may help identify patients at higher risk.
The study demonstrates that WWOX plays a critical role in maintaining epithelial identity in skin cells. When present, WWOX stabilizes the protein p63, a key regulator that preserves normal cell structure and function. Loss of WWOX leads to a significant reduction in p63 levels, triggering a process known as epithelial-to-mesenchymal transition (EMT), in which cells acquire invasive and migratory properties.
“Our findings show that WWOX deficiency significantly accelerates skin cancer onset and progression,” said Prof. Aqeilan. “Understanding this pathway opens new opportunities to identify high-risk patients and develop targeted therapeutic strategies.”
Using advanced genetic models and human tissue samples, the researchers found that tumors lacking both WWOX and the tumor suppressor p53 developed earlier and were more aggressive than those retaining WWOX function. In these models, tumor incidence reached 100% in the double-deficiency group, compared to significantly lower rates in control groups.
Analysis of human tissue samples further supported these findings, revealing that levels of WWOX and p63 decline together as skin cancer advances. This correlation suggests that these proteins could serve as biomarkers to help predict disease progression.
The results also point to potential therapeutic strategies. Approaches aimed at restoring WWOX function, stabilizing p63, or promoting epithelial differentiation may help inhibit EMT and slow tumor growth.
The study, titled “WWOX Maintains Epidermal Identity and Suppresses EMT to Prevent Aggressive Cutaneous Squamous Cell Carcinoma,” is available inPNAS at https://www.pnas.org/doi/10.1073/pnas.2534844123 (DOI: 10.1073/pnas.2534844123).
CONTACT: Danae Marx Hebrew University of Jerusalem 972524334557 danaemc@savion.huji.ac.il
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