Congratulations to Giuseppina Claps, a student in the Sanford-Burnham Graduate School of Biomedical Sciences, on receiving one of ten nationally competitive 2013 Research Scholar Awards from the Joanna M. Nicolay Melanoma Foundation (JMNMF)! These $10,000 grants support exceptional graduate student research in melanoma.
Giuseppina Claps received her JMNMF award at a special recognition ceremony. She is pictured here with her mentor Ze'ev Ronai (left) and Robert Rickert (right), associate dean of the Sanford-Burnham Graduate School of Biomedical Sciences.
Human squamous carcinoma cells with ATF2 (green) located at mitochondria (red) after exposure to genotoxic stress. Nuclei are shown in blue.
The National Cancer Institute (NCI) estimates that as many as one in 51 men and women will be diagnosed with melanoma—the deadliest form of skin cancer—at some point during their lifetimes. A research team led by Ze’ev Ronai, Ph.D. is working to unravel the molecular mechanisms underlying the development and progression of this disease in hopes of improving prevention and treatment strategies. To do this, Ronai’s laboratory has been studying a protein named Activating Transcription Factor 2 (ATF2), which is associated with poor prognosis in melanoma. ATF2 is a two-faced protein—in melanoma cells, it’s oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it acts as a tumor suppressor.
In a paper published February 3 in the journal Cell, the team identified a molecular switch that controls ATF2’s dual functions. This switch is controlled by protein kinase Cɛ (PKCɛ), which disables ATF2’s tumor-suppressing activities, sensitizing cells to chemotherapy; instead, ATF2’s tumor-promoting activity is enhanced. The team also found that high levels of PKCɛ in melanoma are associated with poor prognosis.
Kristiina Vuori, M.D., Ph.D., Sanford-Burnham’s president and director of the Institute’s NCI-designated Cancer Center (Photo by Nadia Borowski Scott)
Sanford-Burnham’s president, Kristiina Vuori, M.D., Ph.D., was named today as part of a new “Dream Team” to find innovative new ways to fight melanoma using a personalized medicine approach.
The Dream Team researchers will receive three years of funding from Stand Up To Cancer and the Melanoma Research Alliance. The newly funded project, which will receive a grant of $6 million, will not only explore a personalized medicine approach to treating metastatic melanoma, but may also lay the groundwork for fighting many other tumor and disease types. Stand Up To Cancer is a program of the Entertainment Industry Foundation, a charitable organization that has raised more than $100 million for cancer research in the past two years, much of it in connection with nationally televised fundraising specials.
“This is a test case to determine whether personalized medicine can become a reality. It’s our hope to be able to treat a patient with melanoma based on that person’s own molecular profile—an approach that’s likely to be more effective and have fewer side effects than current treatments,” said Vuori, who also directs Sanford-Burnham’s National Cancer Institute-designated Cancer Center. “Most importantly, our approach may represent improved survival for this patient group that currently has limited treatment options.”
Melanoma cells, with nuclei in blue and the lncRNA SPRY4-IT1 in green. (Image courtesy of the Perera lab)
Scientists used to think RNA was mostly just a messenger molecule that carries protein-making instructions from a cell’s nucleus to the cytoplasm. But scientists now estimate that 97 percent of human RNA doesn’t actually code for proteins at all. A flurry of research in the past decade has revealed that some types of non-coding RNAs switch genes on and off and influence protein function.
The best studied non-coding RNAs are the microRNAs, but Dr. Ranjan Perera and his collaborators are discovering that levels of a relatively understudied group of RNAs – long, non-coding RNA (lncRNA) – are altered in human melanoma. Their study, published online May 10 by the journal Cancer Research, shows that one lncRNA called SPRY4-IT1is elevated in melanoma cells, where it promotes cellular survival and invasion.
“Non-coding RNA used to be considered cellular junk. But we and others have been asking the question – if it doesn’t code for proteins, what does it do in the cell?” said Dr. Perera, associate professor at Sanford-Burnham’s Lake Nona campus in Orlando, Fla. “We’re especially interested in determining what roles microRNAs and lncRNAs play in the genesis and development of human melanomas.”
Melanoma is one of the rarest forms of skin cancer, but it is also the most deadly.
Anindita Bhoumik, former postdoctoral researcher in the Ronai laboratory
Melanoma is one of the least common types of skin cancer, but it is also the most deadly. Melanocytes (pigment-producing skin cells) lose the genetic regulatory mechanisms that normally limit their number, allowing them to divide and proliferate out of control. One such regulator, called MITF, controls an array of genes that influence melanocyte development, function and survival. Researchers recently used a melanoma mouse model, cell cultures and human tissue samples to unravel the relationship between MITF and ATF2, a transcription factor (or protein that controls gene expression) that is more active in melanomas. The study, published December 23 in PLoS Genetics, demonstrates that the MITF is subject to negative regulation by ATF2, and such regulation is a key determinant in melanoma development. This work also reveals that the ratio of ATF2 to MITF in the nucleus of melanoma cells can predict survival in melanoma patients – relatively high amounts of ATF2 and correspondingly low MITF levels were associated with a poor prognosis.
“In the late 1990s, we began to observe that if you can inhibit ATF2, you can inhibit melanoma,” explained Dr. Ze’ev Ronai, senior author of the study and associate director of Sanford-Burnham’s National Cancer Institute-designated Cancer Center. “This latest study provides the first genetic evidence to support those initial observations. Here we show that mice lacking ATF2 in melanocytes do not develop melanoma even if they carry mutations seen in human melanoma. Moreover, ATF2 expression patterns can predict outcome in melanoma patients.”
Dr. Ranjan Perera with post-doctoral researcher Dr. Joseph Mazar
Skin cancer is the most common cancer in the United States. Melanoma is one of the rarest forms of skin cancer, but it is also the most deadly. At Sanford-Burnham’s Lake Nona campus, Dr. Ranjan Perera’s lab is studying what causes melanocytes (pigment-producing skin cells) to divide abnormally, ultimately forming melanoma. In a study published today in the journal PLoS ONE, a team led by Dr. Perera and post-doctoral researcher Dr. Joseph Mazar show that melanocyte growth and the cancer’s ability to invade other tissue is at least partially controlled by abnormal expression of microRNAs (miRNAs) – small strands of genetic material that may play a major role in numerous diseases by interfering with proteinproduction.“We’ve identified one specific miRNA, called miR-211, that could be used not only as a novel diagnostic marker for early melanoma detection, but also as a therapeutic target,” explains Dr. Perera, associate professor in Sanford-Burnham’s RNA Biology Program and senior author of the study.