Every cell in your body knows what it is. A skin cell knows it is a skin cell; it sits in its proper layer, does its proper job, and does not wander. That identity is not fixed like a birthmark, though. It is actively maintained, continuously, by molecular machinery that has to keep working or the cell begins to drift, shedding its character like a person slowly forgetting their name.
Researchers at the Hebrew University of Jerusalem have now identified one piece of that machinery in skin: a protein called WWOX, which turns out to be far more consequential than anyone appreciated, and whose loss can tip an ordinary skin tumour into something far more dangerous.
Cutaneous squamous cell carcinoma is the second most common form of skin cancer worldwide, and while most cases are caught and treated early, a subset turn aggressive, spreading to lymph nodes and lungs and resisting standard therapies. Those aggressive cases have long been poorly understood at the molecular level. The new work, published in the Proceedings of the National Academy of Sciences, suggests that a large number of them may trace back to the disappearance of this one guardian protein.
The team, led by Prof. Rami Aqeilan, found that WWOX acts as a stabiliser for another protein called p63, a master transcription factor that keeps skin cells doing what skin cells do. Think of p63 as a kind of foreman on a building site, constantly issuing instructions that maintain the structure: build these proteins, maintain these junctions, stay put. WWOX, it turns out, protects that foreman from being sacked. Without it, p63 gets tagged for destruction by an enzyme called the ITCH E3 ubiquitin ligase and is fed to the cell’s disposal system. The foreman disappears. The instructions stop. And the cells, untethered from their identity, start behaving like something else entirely.
That something else is mesenchymal: a migratory, invasive cell type more characteristic of connective tissue than skin. The process of transformation has a name, epithelial-to-mesenchymal transition, and it is one of the more unsettling phenomena in cancer biology, because it converts a locally contained tumour into one that can move.
A Molecular Catastrophe in Two Acts
To demonstrate WWOX’s role, the team used mice engineered to lack WWOX in their skin cells, and combined this deletion with loss of the well-known tumour suppressor p53. Animals missing both proteins developed tumours in every single case, with a median onset roughly five months earlier than mice missing only p53. The tumours were also more poorly differentiated and more likely to display the molecular signatures of EMT. In a separate chemical carcinogenesis model, WWOX-deficient mice developed more lesions, more quickly, even when p53 was still present, suggesting that WWOX suppresses skin tumour formation through mechanisms that extend beyond its partnership with p53.
“WWOX deficiency significantly accelerates tumor onset and progression,” Aqeilan noted, adding that the double-deficiency group reached 100% tumour incidence compared to roughly 65% in the p53-only group.
From Mice to Patients
What makes the study unusual, and arguably more compelling than a pure mouse study, is the human tissue data. The team examined skin cancer samples from a tissue microarray covering patients at different stages of disease. As cSCC advanced from stage I through to stage III, the levels of both WWOX and p63 fell in tandem. The correlation was tight enough to suggest these two proteins could serve as biomarkers, helping clinicians identify early-stage tumours that are headed somewhere bad, rather than waiting for the clinical picture to deteriorate. Genomic profiling of the mouse tumours supported this: WWOX loss triggered a wholesale shift in gene expression, activating pathways associated with inflammation (TNFalpha, interferon), growth signalling (KRAS), and, most prominently, EMT. Some tumour cells in the WWOX-null mice existed in an unsettling halfway state, expressing markers of both epithelial and mesenchymal identity simultaneously, what biologists call a hybrid EMT phenotype. These hybrid cells are increasingly recognised as particularly capable of surviving in the bloodstream and seeding distant metastases.
Human cell lines told much the same story. When WWOX was knocked out in a standard squamous cell carcinoma line, the cells became more migratory and invasive in laboratory assays. They were also more responsive to TGFbeta, a signalling molecule known to drive EMT, showing a greatly exaggerated switch toward mesenchymal identity when exposed to it. And when those WWOX-null cells were injected into the tail veins of mice, they formed significantly larger metastatic colonies in the lungs than WWOX-expressing controls. Restoring WWOX expression reversed these effects, which matters for the therapeutic picture.
There is a complication worth noting. The role of p63 in cancer is not straightforward. In early squamous tumours, p63 can actually act as an oncogene, driving proliferation. It is only later, when a tumour becomes more advanced, that loss of p63 seems to correlate with worse outcomes. The WWOX story fits neatly into that later picture: its absence destabilises p63 at precisely the point in disease progression where p63 loss does the most damage, accelerating dedifferentiation and spread. Whether restoring WWOX function early enough could hold the tumour in a more differentiated state is a question the field will likely pursue.
Targeting tumour suppressors therapeutically is notoriously hard, and WWOX is no exception. You cannot simply give someone a pill that restores a missing protein in the relevant cells. But the new work suggests several indirect approaches worth exploring. The ITCH ubiquitin ligase that degrades p63 in WWOX’s absence is, in principle, a druggable target; blocking it might partially rescue p63 activity even when WWOX is gone. TGFbeta pathway inhibitors are also candidates, given the heightened sensitivity WWOX-null cells display to that signal. And differentiation-promoting therapies, agents that push tumour cells back toward an epithelial identity, have precedent in other cancer types, notably some leukaemias. The fact that WWOX and p63 levels track so closely with disease stage also raises the practical possibility of adding them to the panel of markers used to assess biopsy specimens, potentially catching high-risk cases before they become resistant to treatment.
For a protein with “oxidoreductase” in its name, WWOX has turned out to be unexpectedly social, interacting with more than 300 partners and sitting at the intersection of DNA repair, metabolism, and now epithelial identity. Which raises an obvious question: if its loss is this consequential in skin, how many other cancers are quietly losing their own WWOX, and slowly forgetting what they are meant to be?
It does not “want” anything, but the biology rewards the switch. Epithelial cells are held in place by adhesion molecules and architectural constraints. Mesenchymal cells are migratory by nature, suited to moving through tissue. When a tumour cell undergoes this transition, it gains the ability to invade surrounding tissue and enter the bloodstream, which is how cancers spread. The process is called epithelial-to-mesenchymal transition, and blocking it is one of the active frontiers in cancer research.
WWOX normally protects a protein called p63 from being destroyed. p63 acts as a transcriptional foreman, switching on the genes that define skin cell identity: specific keratins, adhesion molecules, structural proteins. Without WWOX, p63 gets tagged for disposal by a cellular enzyme and degraded. Once p63 is gone, those identity-maintaining genes go quiet, and the cell begins acquiring characteristics of a different, more mobile cell type.
The new research suggests they might. Examining tumour samples from patients at different disease stages, the Hebrew University team found that WWOX and p63 levels dropped in tandem as cancers progressed. If the correlation holds in larger prospective studies, testing for both proteins in biopsies could help flag early-stage tumours likely to behave aggressively, before they have had the chance to spread.
Directly restoring a missing tumour suppressor protein remains technically difficult, but the new findings point toward indirect strategies. The enzyme that destroys p63 in WWOX’s absence is a potential drug target. TGFbeta pathway inhibitors could blunt the heightened EMT response seen in WWOX-null cells. And agents that push tumour cells back toward an epithelial identity, already used in some leukaemia treatments, represent a plausible angle worth exploring in skin cancer.
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