A mutation in a cancer-promoting gene is often considered the first step on the path toward cancer. But just last year, Fred Hutchinson Cancer Research Center postdoctoral fellow Dr. Zhe Ying discovered that instead of accelerating along this path, skin stem cells can respond to these mutations by taking the first exit, using a strategy he dubbed oncogene-induced differentiation. In this phenomenon, a mutation in a cancer-associated gene blocks tumor formation. Instead of pushing cells toward excess division, it causes them to become more specialized and therefore less able to divide.
Now, Ying has received a prestigious, five-year Pathway to Independence Award from the National Institute of Dental and Craniofacial Research, a branch of the National Institutes of Health, to study how certain mutations allow cells to overcome this differentiation barrier in head and neck cancer as he lays the foundation for his independent career.
Ying and his mentor, Dr. Slobodan Beronja, a faculty member in Fred Hutch’s Human Biology Division, unexpectedly found that skin stem cells that carry cancer-promoting mutations in Pik3ca, one of the most commonly mutated oncogenes in cancer, didn’t respond by turning into tumors. Instead they blocked tumor formation by turning into nondividing skin cells.
“Using a model system of stratified epithelium, I found that oncogene-induced differentiation is one of the dominant undescribed tumor-suppressive mechanisms,” Ying said.
Oncogene-induced differentiation joins apoptosis (in which cells undergo programmed death) and senescence (in which cells lose their ability to divide without changing into a new cell type) as a third strategy cells can use to stave off tumor development.
Though Ying’s model system focused on the skin, stratified epithelium is found elsewhere in the body, including the mucus membranes of the oral and nasal cavities. Known as squamous tissue, these cells can give rise to tumors (often grouped together as head and neck squamous cell carcinoma, or HNSCC). In the U.S., more than 65,000 people are expected to be diagnosed with a type of HNSCC, and more than 14,000 will likely die from the disease this year.
Ying is expanding his work into HNSCC because of patient need. The tumors can be difficult to detect compared to skin squamous cell carcinoma and currently no first-line targeted treatment exists. Immunotherapy was recently introduced as a treatment but still doesn’t work for many patients.
“I think our discovery that the pro-renewal lesions are fundamental drivers of HNSCC formation probably would open up another angle for future drug discovery” for these cancers, Ying said.
A key to creating targeted treatments will be figuring out how cells on the path to oncogene-induced differentiation skip the tracks and end up heading back toward tumor development. Ying is examining other mutations in human head and neck cancer that occur with Pik3ca mutations to see which reroute cells toward a cancerous fate.
The Pathway to Independence Award offers two years of funding to help early career researchers gain the skills they need to flourish as independent investigators, and then three years of further funding to help them establish their labs.
During the first two years of his award, Ying plans to take advantage of his mentorship committee and the opportunity to further grow his lab-managing and grant-writing skills as he solidifies the scientific findings that he’ll use to launch his independent career.
Beronja is confident that Ying’s career trajectory will be impressive.
“Zhe is the best and most promising postdoctoral fellow that I have ever worked with,” he said. “There is no doubt that he has what it takes to become an outstanding independent investigator, and I will continue to do whatever I can to help him realize his potential. In my commitment to his career I will try to match Zhe’s commitment to science and my lab.”
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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