Researchers have uncovered the biological processes that convert healthy stem cells into oral cancer at the disease’s onset.
Each year, approximately 60,000 individuals in the U.S. receive an oral cancer diagnosis, as reported by the American Cancer Society, and the number of new cases is continually increasing. A team from the University of California San Diego has now revealed how ordinary stem cells become cancerous in the initial stages of this illness.
Oral cancer, technically referred to as head and neck squamous cell carcinoma, impacts areas such as the mouth, throat, nose, sinuses, and larynx. This type of cancer originates in epithelial cells, which form the outer layer lining these regions. Around 30% of oral cancer cases are linked to human papillomavirus (HPV).
By activating a signaling protein known as YAP (yes-associated protein), which typically plays a role in maintaining and promoting stem cell growth, alongside HPV oncogenes (genes that hinder normal tumor growth suppression), researchers initiated a series of cellular and molecular alterations that converted healthy stem cells into cancer stem cells in a mouse model.
The team employed various cutting-edge technologies to monitor the changes that convert normal stem cells into cancer stem cells at the single-cell level.
This study is groundbreaking as it utilizes advanced methods, including cell tracing (marking cells to observe their growth over time) and multi-omics (which integrates molecular data from genomics, RNA transcription, protein expression, epigenetic modifications, and cellular metabolites to comprehend disease evolution) at the single-cell resolution, allowing researchers to track these changes in real time within a living organism.
According to the senior author, J. Silvio Gutkind, Ph.D., a Distinguished Professor and chair in the UC San Diego School of Medicine’s Department of Pharmacology, and associate director for basic science at UC San Diego Moores Cancer Center, “This allows us to accurately chart how one cell state transitions to another, identifying the very initial events that trigger tumor formation instead of just examining the advanced stages of cancer.”
The researchers observed that activating YAP together with HPV oncogenes:
- led to the development of invasive cancer in only 10 days;
- resulted in the loss of normal cell identity by stopping regular cell differentiation, which caused the cells to adopt a more mobile and invasive nature;
- fueled uncontrolled cell growth by instigating epigenetic changes and activating pathways linked to carcinoma cell proliferation, survival, and movement;
- triggered the release of substances that attracted and altered immune cells, enabling them to dismantle tissue barriers, avoid immune surveillance, and support tumor cell invasion.
Gutkind notes that the next phase will involve applying these methods to investigate how ordinary stem cells transition to cancer stem cells in HPV-negative oral cancers, which are most prevalent among smokers and older patients. His group is also looking into whether new medications that inhibit YAP could offer innovative treatment avenues for oral cancers.
This research is crucial for creating targeted therapies for HPV-positive cancers at their earliest stages. Gutkind mentions that an existing drug, metformin, which is an inexpensive option commonly used to regulate blood sugar in diabetic individuals, shows potential as a candidate. Currently, a clinical trial is in process at UC San Diego to evaluate if metformin disrupts YAP’s function in patients with oral pre-malignancies.
