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No Longer Skimming the Surface of Skin Cancer
Squamous cell carcinoma (top) is a relatively aggressive skin cancer, but it shares many features of lethal solid tumors of the internal organs. The Yuspa laboratory’s efforts to model the biology of skin have given great insight into the genesis and treatment of this and other major skin malignancies, such as basal cell carcinoma (middle) and malignant melanoma (bottom).
When Stuart H. Yuspa, M.D., began studying the skin in the late 1960s, scientists understood some of the basic biology of skin cancer. They knew what was required to produce and diagnose benign and malignant tumors—but not much more. “We’ve made remarkable leaps since then,” says the Co-Chief of CCR’s Laboratory of Cancer Biology and Genetics (LCBG).
“Now we know the genetic changes associated with each stage of cancer development and how those genetic changes translate to biochemistry in each stage,” Yuspa, a specialist in squamous cell skin cancers, explained. “And we have markers to recognize where we are in the progression from normal to malignant.”
Yuspa added, “We also know a lot more about normal skin. We know how skin homeostasis is controlled and the pathways that regulate it. That’s extremely important because you have to understand normal to understand abnormal.” To generate this understanding, over the last 36 years the Yuspa laboratory has developed in vitro models that recapitulate the normal growth and differentiation of skin epithelial cells called keratinocytes—precursors to the squamous cells that give squamous cell skin cancer its name. The models also reproduce each stage of carcinogenesis as it occurs in mouse skin cells.
These model systems have been “really important for understanding mechanisms of cancer,” said Adam Glick, Ph.D., a former Postdoctoral Fellow and Principal Investigator who still collaborates with Yuspa.
And the work is moving from discovery to application. Yuspa, Glick, and their colleagues recently identified genetic markers that distinguish low-risk benign skin tumors from high-risk tumors in mice and opened possibilities for targeted therapies that block early tumors from progressing to invasive lesions.
Yuspa’s models are making inroads for other cancers as well, since similar epithelial cells are involved in cancers of many internal organs, such as the lungs, head and neck, esophagus, colon, and stomach.
A Good Decision
Yuspa first came to NCI in 1967 to work in the lab of Richard R. Bates, Ph.D., who was working on skin carcinogenesis. “There were two of us and a few technicians,” Yuspa recalled. “We did some very nice work looking at carcinogen binding to DNA and how that caused mutations. I loved it! I stayed for the two years of my United States Public Health Service Commissioned Corps obligation, then asked to stay a third.” The young M.D. then left to pursue his clinical training to see what aspect of medicine he liked most—research or clinical work.
“Dick said he’d hold the spot for me, which would be impossible today, but it was the early days of the War on Cancer,” Yuspa continued. After finishing his medical residency training—and realizing that the lab was where he wanted to be—Yuspa returned to the Bates lab to work on the skin model. He became a Senior Investigator at NCI in 1972.
The Place to Be
“Stu’s lab was a place that people came to from all over the world—and still do—to learn how to culture the skin,” according to Molly Kulesz-Martin, Ph.D., who was a Postdoctoral Fellow in Yuspa’s lab from 1979 to 1981 and is now Director of Research and Professor in the Department of Dermatology at Oregon Health & Science University (OHSU).
When Kulesz-Martin joined the Yuspa lab, very few people were working on epithelial cells, even though most human cancers arise from them. “Everybody was working on cells that were easy to grow, but there was no way to assure they were like some particular organ in the body. And they weren’t,” she recalled.
“Stu was working out ways to grow epithelial cells so they behaved as they do in the body. We had to find a way to make culture conditions good for growing epithelial cells,” said Kulesz-Martin. Her work built on earlier laboratory observations that reducing calcium levels enabled cells to grow for much longer than two weeks. From that, she created a transformation assay to quantify the strength of various carcinogens.
Kulesz-Martin’s experiences in Yuspa’s lab set the path for her future as a researcher. At OHSU, she continues to work with mouse and human cells to determine the initial changes and later insults that push a cell from normal to malignant to metastatic. “I didn’t fall far from the tree,” she admitted. “I still want to study cancer, still study skin as a model, and I’m still learning new things about cancer genes that tell us about skin cancer and other kinds of epithelial cancers, such as prostate, liver, and kidney cancers.”
What kind of skin cancer?
The skin’s epidermis harbors the keratinocytes and melanocytes that give rise to skin cancer. The Yuspa laboratory’s efforts to model the biology of skin have given great insight into the genesis and treatment of skin cancers.
Each type of skin cancer—melanoma, basal cell carcinoma, and squamous cell carcinoma—arises in different cells within the skin. Melanoma forms in melanocytes (skin cells that make pigment) and is the most dangerous form of skin cancer. Basal cell carcinoma forms in cells found in the hair follicles. Basal cell cancers are the most frequent human tumor in Caucasians, but they grow slowly and rarely spread to other parts of the body.
Squamous cell carcinoma, the focus of the work of Stuart Yuspa, M.D., begins in squamous cells (flat cells that arise from keratinocytes and form the surface epidermis of the skin). They are not the most frequent skin cancers, but they share many characteristics—genetically and biochemically— with highly lethal cancers that arise in internal organs like the lung, head and neck, esophagus, and stomach.
