Nature Communications: a study co-published by ICGEB Alumnus Dr. Sanjeev K. Waghmare helps reveal how changes in gene regulation can reprogramme cancer cells and promote disease progression.
The new study published in Nature Communications has uncovered a key mechanism that allows some of the most dangerous cells in skin and oral squamous cell carcinomas (SCCs) to survive and fuel tumor growth. The findings not only improve our understanding of how these cancers become more aggressive, but also point to a promising combination therapy that dramatically reduced tumor growth in preclinical models.
Skin and oral SCCs contain small populations of cancer stem cells, a particularly resilient group of cells that can self-renew, drive tumor growth, and often survive conventional treatments. These cells are believed to be one of the main reasons why some cancers recur or become resistant to therapy.
To understand what makes these cells so persistent, the researchers analysed cancer stem cells obtained from SCC patients and compared them with other tumor cells. They discovered that aggressive tumors consistently showed reduced levels of a gene called SFRP1, which normally helps keep cell growth signals under control. Importantly, patients whose tumors had low SFRP1 expression experienced significantly poorer overall survival, both in skin and oral SCC. This suggests that SFRP1 could potentially serve as a biomarker to identify patients at higher risk of aggressive disease.
The researchers discovered that SFRP1 is silenced by an epigenetic modification known as histone methylation. Unlike genetic mutations, epigenetic changes do not alter the DNA sequence itself. Instead, they affect how genes are read and used by cells. Together, these molecules form what the researchers describe as the c-JUN/SOX2/HIF1α axis, a network that helps cancer stem cells maintain their stem-like properties and supports continued tumor growth.
Perhaps the most innovative aspect of the study is that the researchers were able to interrupt this process.
They tested Decitabine, a drug that blocks abnormal DNA methylation and is already approved for certain blood cancers. Treatment restored SFRP1 expression and shut down much of the cancer-promoting signalling pathway. The researchers then combined Decitabine with an inhibitor of RAC1, a protein involved in non-canonical Wnt signaling. By targeting both the epigenetic changes and the signaling pathway that drives cancer stem cells, they achieved a much stronger effect.
In patient-derived models of skin and oral SCC, the combination treatment reduced tumor growth by 75-80%. The therapy also reduced molecular features associated with cancer stemness and reversed some of the metabolic changes that help tumors thrive.
Although the findings still need to be validated in clinical trials, they highlight several important opportunities for the future. First, SFRP1 could serve as a prognostic marker, helping clinicians identify patients with more aggressive forms of SCC. Second, the study suggests that combining epigenetic therapies with drugs that block cancer-promoting signaling pathways may be effective in targeting cancer stem cells, which are often responsible for treatment resistance and disease recurrence.
More broadly, the research demonstrates that cancer progression is not driven by genetic mutations alone. Epigenetic changes can rewire cellular signaling and metabolism, creating conditions that allow tumors to grow and evade treatment.
Dr. Sanjeev K. Waghmare is Group Head of Stem Cell Biology at the Tata Memorial Centre, Kharghar, Navi Mumbai, India. He was an ICGEB Postdoctoral and PhD Fellow in the Microbiology Laboratory at ICGEB Trieste, headed by Dr. Carlo Bruschi. His current work attempts to unravel the molecular mechanisms that control both normal adult stem cells and cancer stem-like cell regulation. His group aims to elucidate the intricate crosstalk between epigenetic modification and metabolic rewiring, which regulate self-renewal and differentiation of stem cells in murine epidermal stem cells, focusing on human skin and oral squamous cell carcinoma.
Link to article: Histone methylation defines c-Jun/Sox2/Hif1α axis that controls stemness and tumor progression in squamous cell carcinoma