Healthy skin cells are able to fight off the cancerous tendencies of nearby cells that harbor cancer-causing, or oncogenic-driver, mutations, according to new work published by Fred Hutchinson Cancer Research Center’s Dr. Slobodan Beronja and colleagues at Yale University. In work published Aug. 2 in the journal Nature, Beronja, with Dr. Valentina Greco at Yale, demonstrated that when skin cells containing oncogenic mutations begin forming disordered growths, neighboring normal skin cells surround the deformed tissue and either push out the growths or convert them into functional skin structures, including new hair follicles.
“We were surprised that there is this interplay between mutant and wild-type cells that is so efficient and so reproducible from one group of cells to the next. It’s an unanticipated repair mechanism,” said Beronja, whose lab studies how normal tissues address mutations or cellular stresses that can cause cancer. “Your skin can tolerate cancer-driving mutations by actively removing the mutated cells.”
The work was an “investigation of plasticity and tolerance mechanisms that exist in cancer-free tissues that bear oncogenic mutations,” Beronja said. Increasingly, studies are finding that healthy tissues harbor a high percentage of cancer-causing mutations — anywhere from 18 to 30 percent in the skin, for example — that don’t actually cause cancer.
“The question is, why?” Beronja said. “What is the plasticity, what is the tolerance mechanism that allows normal tissue, fully functional tissue, to carry on with mutations [and not form tumors]? If there are active mechanisms promoting this plasticity and this tolerance, maybe if we learn more about it we can try to reactivate those mechanisms in the context of cancer.”
The team studied how skin maintains its normal state in the context of two different cancer-driving mutations (activation of the the Wnt/β-catenin signaling pathway and activation of Ras) and in two types of skin cells (hair follicle stem cells and skin stem cells located between hair follicles). Using a specialized method Beronja had developed as a postdoctoral researcher, the scientists were able to control when and where they activated Ras or Wnt/β-catenin in the skin. Then, they tracked in real time how normal and mutated cells grew within the living tissues.
Unlike most scientists examining the effects of cancer-causing mutations, who focus on the tumors that do develop, the team looked at what happened when skin avoided forming tumors.
When they activated either Wnt or Ras signaling in hair follicle stem cells, the scientists found that “indeed, it perturbs the tissue in the way you would expect: It increases proliferation, it deforms the tissue, it results in formation of these cyst-like structures — but only temporarily,” Beronja said.
The normal, unmutated cells, it turned out, actively worked to resolve the tissue deformations by enclosing the overgrown clumps and forcing them out. “Within four weeks, a large number of these structures that you expect would lead to cyst formation and, potentially, eventually cancer fully resolved,” he said. When they activated oncogenic pathways in stem cells between hair follicles, the deformed tissue was often resolved by converting into normal oil-producing glands or new hair follicles.
Physically damaging the bulb region of hair follicles yielded similar results, suggesting that instead of deploying specific strategies based on mutation, skin uses general strategies to overcome damage and literally nip cancerous growths in the bud.
It makes sense that the skin has developed mechanisms to deal with continual attempts by mutated cells to spark tumors, said Beronja, a member of Fred Hutch's Human Biology Division.
“It’s a really high turnover tissue. … Every single progenitor cell divides every two or three days over your lifetime. If [this process] stops, the tissue fails, and if the tissue fails, you die,” he explained. “It makes sense if the skin does get assaulted by constant DNA damage that it does not crumple in the face of that.”
He and his team are currently comparing other high-turnover tissues, such as the mucosal cells that line the mouth, and low-turnover tissues, such as mammary cells that line milk ducts, to see whether cancer-fighting mechanisms that maintain a normal tissue state associate more with cell-turnover characteristics than with the cell type of origin. They are also digging deeper into the specific signals involved in these mechanisms — how they work and how they go wrong and allow tumors to grow.
The study “opens up a lot of investigation into the precise cellular and molecular mechanisms [of the cancer-preventing phenomenon],” said Beronja, who hopes to interest his Hutch peers in collaborations designed to answer both fundamental and translational research questions springing from the work. “How broadly relevant is it? What other tissues should we expect to have a similar ability?” Ultimately, Beronja hopes to produce insights that lead to new ways of treating cancer.
— Sabrina Richards / Fred Hutch News Service
JAMA Oncology, launched in April 2015 and edited by Dr. Mary “Nora” Disis, a translational researcher and faculty member at Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, has received its first journal impact factor, or JIF, which can be used to provide a gross approximation of a journal’s scientific prestige. JAMA Oncology’s debut JIF, 16.6, is one of the highest rankings among oncology journals, coming in at No. 8 in total citation frequency out of 217 scientific cancer publications worldwide, according to Journal Citation Reports, which is published by Clarivate Analytics (formerly Thomson Reuters).
Simply put, a JIF is the average number of times that a journal’s articles have been cited in the past two years. So, JAMA Oncology’s impact factor of 16.6 can be interpreted to mean that in the past two years, its articles have been cited, on average, more than 16 times each.
“It is truly impressive to enter the field with this metric,” said Dr. Nancy E. Davidson, senior vice president and director of the Clinical Research Division at Fred Hutch, of which Disis, the journal’s editor in chief, is a member. “We are fortunate that one of our own Seattle cancer research leaders is making such an impact in oncology internationally,” said Davidson, who is also professor and head of the UW Division of Medical Oncology and president and executive director of Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner.
Disis is an expert in breast and ovarian cancer immunology and immunotherapy. Her research focuses on the discovery of new molecular targets to be used in the development of vaccines and T-cell therapies for these cancers.
In addition to being a clinical researcher at Fred Hutch and a co-investigator in the Hutch-based Cancer Immunotherapy Trials Network, Disis holds many appointments within UW School of Medicine, including associate dean for Translational Health Sciences, director of the Center for Translational Medicine in Women’s Health and professor of medicine in the Division of Medical Oncology.
JAMA Oncology, published by the American Medical Association, covers all aspects of medical, radiation and surgical oncology and related subspecialties. It is part of the JAMA Network, which includes 16 publications. JAMA Oncology is published online weekly and in print monthly. The journal reaches more than 24,000 oncologists each week and receives more than 1.1 million online visits annually.
In an editorial to introduce the new journal, Disis wrote in its inaugural issue: “It’s an incredible time to be a researcher and clinician in the field of oncology. New markers, treatments, and entire practice patterns are emerging as we work to keep pace with a torrent of new data. … We will work to ensure that our scientific and educational content provides a deeper understanding of cancer pathogenesis and recent treatment advances. Most of all, we are excited to make JAMA Oncology the journal that none of us can live without!”
If the journal’s out-of-the-gate impact factor is any indication, it appears she already has made good on her promise.
— Kristen Woodward / Fred Hutch News Service
The Damon Runyon Cancer Research Foundation has named Dr. Jeremy Roop, a postdoctoral research fellow at Fred Hutchinson Cancer Research Center, a Damon Runyon Fayez Sarofim Fellow. He is among 18 new Damon Runyon Fellows, the foundation announced in mid-July.
Recipients of this prestigious early-career award are outstanding postdoctoral scientists who conduct fundamental and translational research in the laboratories of leading senior investigators across the U.S.
Roop, who works in two research laboratories at Fred Hutch — that of HIV researcher, award sponsor and mentor Dr. Julie Overbaugh of the Human Biology Division and that of evolutionary and computational biologist and mentor Dr. Jesse Bloom of the Basic Sciences and Public Health Sciences divisions — seeks to advance HIV vaccine-design efforts by studying the unique antibody responses of infants infected with the virus. Antibodies are precision molecules produced by the immune system that are a key part of the body's response to disease.
“I am deeply grateful for the support given by the Damon Runyon Foundation for my research,” said Roop, whose fellowship will provide $231,000 in funding over four years. “Pursuit of my research goals will require the development of new computational and experimental methods, and the support of the Damon Runyon Foundation will greatly assist in this process.
“Additionally, the allowance that the foundation gives for travel to scientific conferences will be extremely useful as I eventually seek to integrate my work into that of the larger HIV research community,” he said.
The 36 million people worldwide who are infected with HIV are also at an increased risk for many forms of cancer due to their compromised immune systems. Infants who acquire the virus from their mothers rapidly develop broadly active antibodies that can neutralize a wide diversity of global HIV strains.
An understanding of the developmental processes involved in eliciting this broad and potent immune response may reveal clues vital to vaccine-design efforts. Roop’s research will develop a novel experimental protocol that will allow a detailed characterization of these infant antibodies, as well as reveal insights into the unique developmental processes by which they arise.
— Based on a Damon Runyon Cancer Research Foundation news release