Scientists identify molecular switch that may predict aggressive skin cancer
A molecular “switch” that helps skin cells maintain their identity may determine whether a common form of skin cancer remains treatable or becomes an aggressive, metastatic disease, Israeli scientists announced.
Israelis hit the beach in Tel Aviv during a heat wave on July 4, 2024. Photo by Gideon Markowicz/TPS
The Hebrew University of Jerusalem study focused on cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer worldwide. This subset can become invasive and spread to other organs, making early identification of high-risk tumours a major clinical challenge. Globally, cSCC is thought to affect millions of people each year, though precise figures are difficult to establish because many countries do not systematically register non-melanoma skin cancers.
Researchers led by PhD student Tirza Bidany-Mizrahi under Prof. Rami I. Aqeilan, working with colleagues in Italy, identified a molecular pathway centred on a protein called WWOX. The team describes WWOX as a “guardian” of epithelial identity — the stable state that keeps skin cells functioning in their normal, organised form.
The study shows that WWOX stabilises another key protein, p63, a master regulator of skin cell structure and differentiation. When WWOX is present, p63 levels remain stable, and cells retain their normal identity. When WWOX is lost, p63 levels fall sharply, and this stability breaks down.
This loss of cellular identity can trigger epithelial-to-mesenchymal transition (EMT), a process in which cells shed their fixed characteristics and gain the ability to migrate and invade surrounding tissues. In cancer, EMT is a critical step that enables tumour spread.
The findings were published in the peer-reviewed Proceedings of the National Academy of Sciences.
“What this study adds is the upstream control mechanism,” the researchers explain, noting that WWOX sits above p63 in this regulatory hierarchy and helps maintain its stability, preventing the cascade that leads to invasion.
In laboratory models, loss of WWOX combined with disruption of the tumour suppressor p53 led to earlier and more aggressive tumour formation. “WWOX deficiency significantly accelerates tumour onset and progression,” Prof. Aqeilan noted, adding that “100% of the subjects in the double-deficiency group developed tumours, compared to a much lower percentage in the control groups.”
Importantly, the findings were not limited to experimental models. In human tumour samples, researchers observed a consistent pattern: as cSCC progressed to more advanced stages, both WWOX and p63 levels declined together. This parallel drop suggests the pathway is active in patients and not just in the laboratory setting.
The novelty of the study lies in identifying the WWOX–p63 axis as a regulator of whether skin cancer cells maintain stability or acquire invasive potential, and in linking it to disease progression in human tissue. The researchers suggest it could eventually help identify patients at higher risk of aggressive disease and offer a new target for therapies aimed at preventing metastasis.
One immediate application is improved risk assessment in cSCC. Clinicians currently rely on tumour size, depth, and histology to estimate aggressiveness. WWOX and p63 levels could add a molecular marker to that framework. Because both proteins decline together as disease advances, low levels may signal that a tumour is already shifting toward a more invasive state, allowing earlier identification of high-risk patients and closer monitoring or more intensive treatment.
Moreover, because the EMT transition is a core process in many epithelial cancers, including lung, breast, colon, and head and neck cancers, the findings raise the possibility that restoring WWOX function or stabilising p63 could help keep cancer cells in a less invasive state.
