Investigators

Summary

The work of our group (jointly directed by Patrick Moore and Yuan Chang) has focused on human tumor viruses since the early 1990s when we identified Kaposi's sarcoma associated herpesvirus (KSHV/HHV8) and showed that this virus was causally associated with Kaposi's sarcoma, the most common AIDS-related cancer in the United States and the most common malignancy in parts of Africa. We sequenced the KSHV genome, developed serologic assays, determined its prevalence in human populations, and characterized many of its critical viral oncoproteins. We have continued to study virus-host cell interactions in the context of dysregulation of pro-proliferative and anti-apoptotic pathways. We recently identified the seventh human tumor virus, Merkel cell polyomavirus (MCV), from a Merkel cell carcinoma (MCC). We characterized the transcriptional products of MCV and described the early region viral T antigen oncoproteins. Our work has established that MCV causes ~80% of MCC: we determined that the virus is clonally integrated in MCC tumor cells; that human tumor-associated Large T (LT) antigens contain signature truncation mutations; that T antigen proteins are expressed in MCC tumor cells by novel antibodies we developed; and we are the first laboratory to show rodent cell transformation by MCV sT antigen but not the LT antigen. We have identified several novel cellular interactors for MCV T antigens that open new avenues of investigating critical oncogenic signaling pathways. We have focused on many aspects of cancer etiology as modeled through oncogenic tumor viruses.

Summary

Dr. Moore focuses his research on the link between viruses and cancer. Through his research, he hopes to answer why some viruses evolve to cause cancer while others cause nothing worse than the common cold. Dr. Moore and his wife, Yuan Chang, MD, discovered Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8. KSHV causes Kaposi’s sarcoma, the most common malignancy occurring in AIDS patients. Kaposi’s sarcoma, a disease in which cancer cells are found in the tissues under the skin or mucous membranes, can be very aggressive in people whose immune systems are suppressed. Prior to this discovery, scientists had worked for 20 years to find an infectious agent associated with Kaposi’s sarcoma. He and Dr. Chang also are the discoverers of Merkel cell polyomavirus, which is the culprit that causes the rare and deadly skin cancer, Merkel cell carcinoma.

Summary

Joseph T. Newsome is an Associate Professor in the Department of Pathology and Associate Director – Division of Laboratory Animal Resources at the University of Pittsburgh. He is also the Director of the UPMC Hillman Cancer Center Animal Facility Shared Resource. He is a team member of the Cancer Virology Program. His current focus and expertise are in management, biosecurity, biocontainment, facility design and operations, and cancer modeling, immunology, and virology. He is involved in national and industry level organizations such as the American College of Laboratory Animal Medicine, the Association of Primate Veterinarians, the Association of Laboratory Animal Science, The NASEM ILAR Roundtable, and the American Veterinary Medical Association. Newsome received a B.Sc. in microbiology, an M.S.  in pathobiology, and a DVM from the Ohio State University College of Veterinary Medicine. He is certified as a Diplomate of the American College of Laboratory Animal Medicine.

Summary

Studies on animal polyomaviruses have provided a wealth of information for cancer biology. Research on the simian and murine polyomaviruses (SV40 and PyV) led to the discovery of tumor suppressor proteins p53 and retinoblastoma (pRb) and unveiled the importance of tyrosine kinase activities in tumorigenic signaling. Our research exploits the human Merkel cell polyomavirus (MCV) that causes most Merkel cell carcinoma (MCC), a rare but deadly skin cancer that exhibits similarity to the tactile sensor “Merkel cells”. Despite the rarity of MCC, MCV infection is common, and nearly all healthy adults were asymptomatically infected and shed MCV from their skin. MCV is a small circular DNA virus that persists in currently unidentified dermal cells. There are two accidental events that are essential for MCV tumorigenesis and act as triggers that turn this common virus into a cancer-causing virus: insertion of linearized viral DNA into host cellular genome and introduction of a specific mutation that inactivates the viral replication enzyme.

By using molecular and cell biological approaches, our lab investigates: (1) MCV lifecycle processes, especially viral DNA replication, gene expression, and viral progeny production (2) MCV target cells wherein MCV persists or transforms into MCC, (3) biological triggers that disrupt the circular MCV DNA and facilitate insertion into host genome, and (4) critical cellular signaling activated by MCV proteins that promote MCC carcinogenesis. A full understanding of these events will help us prevent MCV-associated MCC, as well as identify therapeutic strategies for this deadly cancer.