Investigators

Summary

My long-term goal is to understand how perturbation of chromatin regulators disrupts the epigenome to affect fundamental epigenetically controlled processes. To address this question, I study genetic alterations in chromatin regulators that occur in sarcomas and other solid tumors. By combining my experience in pharmacology, genetics, chromatin biology, and sarcoma medical oncology, I am focused on addressing three major questions: 1) What are the effects of newly recognized cancer-associated histone mutations? 2) How do sarcoma-associated genetic alterations in chromatin regulators affect chromatin organization and function? 3) How might these alterations be targeted therapeutically?

In addition, I care for adult patients with sarcoma as a medical oncologist. I strive to encourage collaboration between my clinical and basic science colleagues by bringing my knowledge of both spheres into my work with others. Within my own group's, my goal is to develop projects that ultimately allow us to translate our laboratory discoveries back to the clinic to help patients.

Summary

Yana G. Najjar, MD is a translational investigator and cutaneous oncologist at the UPMC Hillman Cancer Center, where she is an Associate Professor of Medicine and Director of the Clinical and Translational Research Center. Dr. Najjar specializes in the treatment of advanced melanoma, focusing on anti-PD1 resistant melanoma and rare melanoma subtypes. Using a bench-to-bedside approach, she has developed multiple investigator-initiated trials that aim to remodel melanoma tumor cell metabolism and hypoxia in the tumor microenvironment to overcome mechanisms of resistance to immunotherapy. Her lab is focused on various correlative analyses from investigator-initiated trials. Dr. Najjar's research is funded by the NIH, the Department of Defense and the Melanoma Research Alliance.

Summary

CENP-A is a heritable epigenetic mark that determines centromere identity and is essential for centromere function. Centromeres are the central genetic element responsible for accurate chromosome segregation during cell division, and as such, they are anticipated to be evolutionarily stable. How centromeres evolved to allow faithful chromosome inheritance on an evolutionary timescale despite their epigenetic maintenance is unclear. One of our interests is understanding whether CENP-A is capable of precisely and stably specifying human centromere position throughout cellular proliferation. To investigate the positional stability of human centromeres as cells proliferate, we use a fibroblast cell line that harbors a neocentromere (epigenetic stable acquisition of a new centromere at a new chromosomal site).

Studying human centromeres epigenomics is challenging since human centromeres are found at unique DNA sequences, termed a-satellite, that is highly repetitive. Another research interest of our lab is tackling this challenging DNA and the histones and proteins bound to it, by using novel epigenomics tool such as DiMelo-seq that is a long-read, single-molecule method for mapping protein–DNA interactions genome wide. This method is essentially ChIP-seq on long-reads DNA sequences that can be sequenced using Oxford nanopore long-read sequencing. We are excited to determine the centromeric DNA sequences associated with different centromeric proteins across the cell cycle and how these may change when centromeric proteins are highly expressed, as seen in cancer, using this method.

CENP-A is highly expressed in several cancers, serving as a marker of poor prognosis. When overexpressed, CENP-A is ectopically loaded onto non-centromeric transcriptionally active sites. Ectopic CENP-A sites are removed during DNA replication to restrict CENP-A to the centromeres only, ensuring faithful chromosome segregation during mitosis and maintenance of genome stability. Induced overexpression of CENP-A in cancerous cells has been shown to lead to chromosome segregation defects and micronuclei formation. Whether the sole overexpression of CENP-A in non-transformed near-diploid cells can induce genomic instability that can drive tumor formation remain poorly understood and is another focus of our lab research.

Summary

I am an assistant professor of radiology and the co-director of the preclinical in vivo imaging facility (IVIF) at UPMC Hillman Cancer Center. I have expertise in molecular imaging (PET, SPECT, optical), organic synthesis, peptide synthesis, conjugation and radiochemistry, targeted radiotherapy (α and β), and animal model of cancer. My research focus is on the development of novel radiopharmaceuticals for molecular imaging and targeted radiotherapy therapy. As the co-director of the IVIF I help investigators incorporate pre-clinical imaging to enhance their research through the IVIF as well as develop novel targeted. In addition, the IVIF provides laboratory support for clinical trials investigating radiopharmaceuticals at UPMC.

Summary

The main interest of the Neumann laboratory is to expand our knowledge of cell signaling that is in part mediated by oxidation and reducing (redox) reactions as reactive oxygen species (ROS) deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis, including breast cancer. To investigate the specific mechanisms underlying redox-induced tumorigenesis, the Neumann laboratory focuses on the redox-induced posttranslational modifications (PTM) of protein cysteines, which are essential in cell signaling. Peroxiredoxin 1 (PRDX1) is a peroxidase that has emerged as a critical protein in cell signaling as it scavenges the second messenger H2O2, binds to and regulates signaling proteins, and when knocked out in mice, causes a variety of cancers, including breast cancer. 

Using this system, we have identified protein cysteines modified by ROS, contributing to breast cancer initiation and progression. For example, we have discovered that a previously unknown functionally essential cysteine in the recombinase RAD51 is vital for its function in homologous recombination-mediated DNA repair. Based on these findings, we have developed a reversible, non-toxic covalent inhibitor that targets this functionally essential RAD51 cysteine, thus inhibiting RAD51 function and, significantly, sensitizing triple-negative breast cancer cells to DNA-damaging therapies. Current work in the laboratory is geared towards successfully  IND-labeling the inhibitor and further discovering other functional protein cysteine targets that can be exploited as anti-cancer therapies.

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

Dr. Nikiforov's research is focused on thyroid cancer genomics and mechanisms of chromosomal rearrangements and other mutations induced by ionizing radiation in thyroid cells and other cell types. Since 2000, Dr. Nikiforov's research activities have led to four scientific discoveries. These discoveries described below have resulted in more than 120 published papers and form the basis of Dr. Nikiforov's current work. 1.The discovery that genes involved in recurrent chromosomal rearrangements in cancer cells are localized in proximity to each other in the nuclei of normal human cells at the time of exposure to ionizing radiation or other genotoxic stress (Science, 2000, 290:138-141). 2.The discovery that BRAF oncogene can be activated as a result of chromosomal rearrangement (J Clin Invest, 2005,115:94-101). 3.The discovery that in thyroid cancer, chromosomal rearrangements represent the main mutational mechanism in tumors arising as a result of exposure to ionizing radiation, whereas point mutations are a mechanism of spontaneous (chemical) carcinogenesis (J Clin Invest, 2005,115:94-101). 4.The discovery of ALK activation in thyroid cancer as a result of STRN-ALK fusion (PNAS, 2014, 111:4233-8). Current research activities of Dr. Nikiforov's lab are focused on further understanding the molecular mechanisms of radiation-induced carcinogenesis and chromosomal rearrangements in human cells. Specifically, the studies aim to establish the number of double-strand DNA breaks required for the formation of a chromosomal rearrangement after exposure to ionizing radiation and identify the DNA repair mechanisms involved in this process. The results of this research will allow better understanding of carcinogenesis induced by ionizing radiation and help to develop measures for alleviating and preventing the carcinogenic effect of radiation exposure. Another direction of Dr. Nikiforov's research is centered on finding novel mutations and gene fusions in thyroid cancer using next-generation sequencing and applying the current knowledge in molecular genetics of thyroid cancer to the clinical management of patients with thyroid nodules. Specifically, the studies in progress aim to define the diagnostic utility of molecular markers for preoperative diagnosis of cancer in thyroid fine-needle aspiration (FNA) biopsies and to characterize several novel chromosomal rearrangements discovered in thyroid cancer by next generation sequencing.

Summary

Dr. Marci Lee Nilsen is a nurse scientist dedicated to advancing research in the realm of head and neck cancer survivorship. Her research program is centered on enhancing the quality of life and overall survival of individuals within this population by characterizing predictors and trajectories of symptoms and treatment-related effects, with a specific emphasis on pain, musculoskeletal disorders, and cognition. Dr. Nilsen’s current National Cancer Institute MERIT grant focuses on characterizing trajectories of radiation-induced fibrosis, co-occurring treatment effects, and the clinical and biological factors that impact these trajectories. Her ultimate goal is to develop tailored, patient-centered interventions aimed at mitigating these symptoms and the co-occurring adverse treatment effects that continue to impact survivors of head and neck cancer throughout their survivorship journey. Furthermore, Dr. Nilsen's work focuses on implementing evidence-based practices in resource-limited settings, aiming to deliver equitable, person-centered cancer care. She is also the co-founder and co-director of the UPMC Head and Neck Cancer Survivorship Clinic.