Research alert: How healthy stem cells turn into oral cancer

Nearly 60,000 people are diagnosed with oral cancer in the U.S. every year, according to the American Cancer Society, and the rate of new cases continues to rise. Now, researchers at University of California San Diego have discovered how healthy stem cells are transformed into cancer stem cells in the earliest stages of the disease.

Oral cancer — also known as head and neck squamous cell carcinoma — affects the mouth, throat, nose, sinuses and voice box. The cancer takes root in epithelial cells, the top layer of cells lining these cavities. Around 30% of oral cancer cases are caused by human papillomavirus (HPV).

By activating a signaling protein called YAP (yes-associated protein, a transcription factor normally involved in stem cell maintenance and growth promotion) in combination with HPV oncogenes (genes that inhibit the normal suppression of tumor growth), the researchers triggered a cascade of cellular and molecular changes that reprogrammed normal stem cells into cancer cells in a mouse model.

The researchers used several state-of-the-art technologies to trace the progression of changes that transformed healthy stem cells to cancer stem cells at the resolution of the single cell.

The study is the first to use technologies such as cell tracing (marking cells to follow their proliferation through time) and multi-omics (analyzing molecular data from genomics, RNA transcription, protein expression, epigenetic changes and cellular metabolites to understand disease development) at the resolution of single cells to follow the real-time progression of these changes in a living organism.

“We can understand precisely how you go from one cell state to another cell state and identify the very, very early events in tumor initiation rather than the final state of cancer,” said senior author J. Silvio Gutkind, Ph.D., Distinguished Professor and chair at UC San Diego School of Medicine Department of Pharmacology, and associate director for basic science at UC San Diego Moores Cancer Center.

The researchers found that activating YAP in combination with HPV oncogenes:

• resulted in invasive cancer within just 10 days;
• caused a loss of normal cell identity by halting normal cell differentiation, leading to the acquisition of a more mobile and invasive state;
• promoted unrestrained cell proliferation by promoting epigenetic changes and stimulating pathways related to carcinoma cell growth, survival, and migration; and
• resulted in the secretion of factors that recruited and reprogrammed immune cells to break down tissue barriers, evade immune detection, and facilitate tumor cell invasion.

Gutkind says the next step is to use the same technologies to understand what leads to the progression of normal stem cells to cancer stem cells in HPV-negative oral cancers, which are most common in smokers and older patients. His team is also exploring whether recently developed drugs that block YAP function may provide new treatment options for oral cancers.

He adds that the research paves the way for the development of therapeutics to target HPV-positive cancers at their very earliest stages. He notes that an existing drug, metformin, an inexpensive medication which has long been used to control blood sugar in diabetic patients, is one promising candidate. A clinical trial is currently underway at UC San Diego to test whether  metformin interferes with YAP, for example, in patients with oral pre-malignancies.

The study was published on January 8 in Nature Communications. 

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