April 20, 2026 – A newly identified biological mechanism that acts as a primary defense against the progression of aggressive skin cancers, such as cutaneous squamous cell carcinoma (cSCC), has been uncovered by researchers at the Hebrew University of Jerusalem (HU). The study was led by Ph.D. student Tirza Bidany-Mizrahi under the guidance of Prof. Rami I. Aqeilan of the Lautenberg Center for Immunology and Cancer Research at the HU Faculty of Medicine, in collaboration with researchers from the University of Rome.

cSCC is the second most common skin cancer worldwide. While many cases are treatable, some tumors become highly aggressive, spreading to other parts of the body and becoming resistant to standard therapies. The findings, published in PNAS, provide a new roadmap to identify which patients are at the highest risk.

The study explains how the loss of the protein called WWOX allows common skin cancer cells to transform into a more lethal, invasive form. The HU research team found that WWOX serves as a “guardian” of what scientists call epithelial identity. In healthy skin, this protein ensures that skin cells remain stable and perform their intended functions. When WWOX is present, it stabilizes another essential protein known as p63, which acts like a master switch to keep skin cells from losing their shape and structure.

Using advanced genetic models and human tissue samples, the team demonstrated that when WWOX is lost, the p63 protein levels drop significantly. This creates a “perfect storm” for cancer progression. Without these two protectors, skin cells undergo a process called epithelial-to-mesenchymal transition (EMT). Essentially, the cancer cells lose their “skin cell” identity and acquire the characteristics of migratory cells, allowing them to invade deeper tissues and move through the bloodstream to the lungs and other organs.

The study reveals that the loss of WWOX does not just make cancer possible; it dramatically accelerates it. In laboratory models in which both WWOX and the well-known tumor suppressor p53 were absent, tumors appeared much earlier and were far more aggressive and poorly differentiated than those where WWOX was still functioning.

“WWOX deficiency significantly accelerates tumor onset and progression,” Prof. Aqeilan noted, adding that 100% of the subjects in the double-deficiency group developed tumors compared to a much lower percentage in the control groups.

The research paper titled “WWOX Maintains Epidermal Identity and Suppresses EMT to Prevent Aggressive Cutaneous Squamous Cell Carcinoma” is now available in PNAS and can be accessed here.

Title: WWOX Expression Correlates with Elevated p63 Levels in Skin Cancer Cells
Description: Immunofluorescence staining showing that overexpression of WWOX (green) in A431 cells is associated with increased levels of p63 (red).
Credit: Tirza Bidnay-Mizrahi

Researchers:

Tirza Bidany-Mizrahi1, Kian Maroun1, Mara Mancini2,3, Osama Hidmi1, Ihab Ansari4, Jonathan Monin1, Tal Keidar Haran5, Alexander Maly5, Gerry Melino2,3, Eleonora Candi2,3 and Rami I. Aqeilan1,6

Institutions:

  1. The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
  2. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy
  3. IDI-IRCCS “Istituto Dermopatico dell’Immacolata”, Biochemistry Laboratory, Rome, Italy
  4. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel
  5. Department of Pathology, Hadassah University Hospital, Jerusalem, Israel
  6. Cyprus Cancer Research Institute (CCRI), Nicosia, Cyprus.