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Wistar Science Highlights: Advances in Melanoma Biology, New Generation Immunotherapy for Antibiotic-resistant Bacterial Infection, New Aspects of the 3-D Organization of the Genome, and Wistar Scientist Selected for NIH Award

Over the past month, Wistar scientists have published new studies on fundamental aspects of melanoma metastasis and therapy resistance, the application of a novel immunotherapeutic technology to prevent infection with antibiotic-resistant bacteria, and the discovery of new aspects of the three-dimensional organization of the genome. Also, the National Institutes of Health (NIH) selected a Wistar principal investigator for her innovative epigenetics research.

Two important studies shed light on fundamental aspects of melanoma biology, both conducted in the lab of Meenhard Herlyn, D.V.M., D.Sc., Caspar Wistar Professor in Melanoma Research, director of Wistar’s Melanoma Research Center and professor in the Molecular and Cellular Oncogenesis Program.

The first study led to the identification of a slowly proliferating and highly invasive melanoma cell subpopulation, characterized by their production of SerpinE2, a protein associated with invasive behavior. The pattern of metastatic dissemination in advanced melanoma is unpredictable because of the biological and genetic heterogeneity that characterizes melanoma cells.

Herlyn and colleagues demonstrated that the slowly proliferating cell population is highly invasive and that SerpinE2 is critical for melanoma invasion. Higher expression levels of this protein in patients correlated with disease progression. Because SerpinE2 is expressed by melanoma cells and not by normal skin cells, it may be a potentially useful tool for early detection of isolated invasive cells. It may also potentially be used as a novel target to prevent or limit melanoma dissemination.

Another study, conducted by the Herlyn lab in collaboration with the University of Pennsylvania, uncovered how melanoma cells rewire their signaling pathways to develop resistance to drug treatment, causing most patients to relapse. Study results, published in Nature, focused on the molecular alterations that occur in melanoma cells when patients receive the recently developed combination therapy that targets simultaneously two main melanoma signaling pathways. This therapy is initially successful in extending the lives of patients with this aggressive disease, but unfortunately, after several months of treatment almost all patients on the regimen eventually relapse.

Herlyn and collaborators characterized the alternative pathway that melanoma cells activate to circumvent the therapeutic block. This pathway is governed by a family of proteins called PAK, and treatment of cells that are resistant to combination therapy with a PAK inhibitor reduced their ability to grow. This observation may help direct the design of novel therapeutic strategies to overcome acquired drug resistance.

“When cancer gets smart, we have to act even smarter,” said Herlyn.

New research by the lab of David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, in collaboration with MedImmune, LLC and Inovio Pharmaceuticals describes the application of a novel immunotherapeutic technology to prevent infection with antibiotic-resistant bacteria. This investigational technology, called DNA-encoded monoclonal antibody (DMab), uses synthetic DNA to encode protective antibodies that are engineered to be directly generated in the body against specific bacterial antigens.

Antibiotic resistant Pseudomonas aeruginosa is a frequent cause of pneumonia and skin infections in immunocompromised individuals and is a leading cause of hospital-acquired infections. In the study, Weiner and collaborators described the use of DMAb technology in a mouse model of pneumonia caused by P. aeruginosa lung infection. The delivery of DMAbs enabled mice to directly produce their own protective antibodies against the bacteria.

“More than 2 million cases of antibiotic-resistant infections are reported each year in the United States alone, imparting a significant global health and economic burden,” said Weiner. “This study provides a potential new approach to the treatment of bacterial infections and illustrates possible advantages of having the body produce its own designer antibody molecules.”

Wistar researchers have uncovered new aspects of the three-dimensional organization of the genome, specifically how the genetic material is compacted and de-compacted in a timely fashion during the different phases of the cell cycle. Genetic information contained inside each of our cells is encoded by several feet worth of DNA molecules that are packed into a microscopic space in a highly organized complex of DNA and proteins called chromatin. Chromatin needs to be further condensed when the cells prepare to divide, in order to faithfully segregate the genetic material. This process has been known for several decades, yet the underlying molecular mechanisms that govern chromatin condensation and de-condensation are still poorly defined.

Ken-ichi Noma, Ph.D., associate professor in Wistar’s Gene Expression and Regulation Program, and colleagues dissected the condensation and de-condensation of chromatin in topological domains over time. In previous studies, they discovered that two protein complexes called condensin and cohesin mediate the formation of functional genome-organizing structures called topological domains by establishing contacts that bring distantly located DNA regions closer together. Following the formation and decay of chromatin contacts over time, the researchers described the fate of the different types of topological domains during the cell cycle of the fission yeast, which is used as a model organism because it shares some important features with human cells while having a much smaller genome. Alterations of the three-dimensional structures of the genome are linked to genetic diseases and cancer, presenting a powerful example of how basic cellular processes are relevant for disease.

Kavitha Sarma, Ph.D., assistant professor in Wistar’s Gene Expression and Regulation Program, was selected for the National Institutes of Health (NIH) Director’s New Innovator Award (DP2) for her research on epigenetic regulation during transcription. This $1.5 million award, given over five years, will further Sarma’s research efforts to understand chromatin based mechanisms of neurodegeneration and identify new therapeutic targets in these diseases.

The NIH DP2 Award initiative supports a small number of early stage investigators of exceptional creativity who propose bold and highly innovative new research approaches that have the potential to produce a major impact on broad, important problems in biomedical and behavioral research. The NIH Director’s New Innovator Award initiative is a component of the High Risk - High Reward Research Program of the NIH Common Fund and complements ongoing efforts by NIH and its Institutes and Centers to fund early stage investigators.