A groundbreaking study from researchers at the University of California, San Diego (UCSD) has uncovered how healthy stem cells can be transformed into cancer stem cells at the earliest stages of oral cancer. The study offers crucial insights into the mechanisms driving the development of head and neck squamous cell carcinoma, a type of cancer that affects areas such as the mouth, throat, and voice box.
According to the American Cancer Society, nearly 60,000 people in the U.S. are diagnosed with oral cancer each year, and the incidence rate is on the rise. Approximately 30% of oral cancer cases are linked to human papillomavirus (HPV), a virus known to play a significant role in tumor development. The disease begins in epithelial cells, which make up the top layer of cells in these cavities.
The UCSD research team found that the activation of a protein called YAP (Yes-associated protein), which is typically involved in stem cell growth and maintenance, in combination with HPV oncogenes, triggers a series of cellular and molecular changes that reprogram healthy stem cells into cancerous cells. This discovery was made using cutting-edge techniques that allow researchers to track the transformation of stem cells into cancer stem cells at a single-cell resolution in a mouse model.
This study is the first to use advanced technologies such as cell tracing and multi-omics analysis to examine the real-time changes that occur during tumor initiation. These methods enable a deeper understanding of how cancer develops from its earliest stages, rather than focusing on the end-stage tumor.
“We can now pinpoint the specific early events that lead to tumor formation,” said Dr. J. Silvio Gutkind, senior author of the study, Distinguished Professor, and Chair of the UC San Diego School of Medicine’s Department of Pharmacology. He is also the Associate Director for Basic Science at the UC San Diego Moores Cancer Center.
The research revealed that when YAP was activated in conjunction with HPV oncogenes:
- Invasive cancer developed in just 10 days.
- The transformation caused a loss of normal cell identity and halted regular cell differentiation, pushing the cells into a more mobile and invasive state.
- The changes led to uncontrolled cell proliferation, triggered by epigenetic modifications and pathways related to cancer cell growth, survival, and migration.
- Additionally, cancer cells secreted factors that recruited and reprogrammed immune cells to break down tissue barriers, evade immune detection, and facilitate further tumor invasion.
Looking ahead, Dr. Gutkind and his team plan to apply the same technologies to investigate how normal stem cells become cancer stem cells in HPV-negative oral cancers, which are more commonly seen in smokers and older patients. Another key area of focus is exploring whether drugs that block YAP could offer new treatment options for oral cancers.
The research also opens the door for new therapies targeting HPV-positive cancers at their earliest stages. One potential treatment already being explored is metformin, a widely used and inexpensive drug for controlling blood sugar in diabetes patients. A clinical trial is currently underway at UC San Diego to test whether metformin can interfere with YAP function and prevent the development of oral pre-malignancies.
This study marks a significant advancement in cancer research and brings researchers closer to developing treatments that could halt the progression of oral cancer before it even begins.
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