Cancer Biology (CB)

Epstein-Barr Virus

Ann Marie Pendergast, PhD

Program Co-Leader

Micah Luftig, PhD

Program Co-Leader

Program Overview

This program is the single broad-based basic cancer science research program in the DCI. The CB program provides a critical hub for basic research in the areas of cancer cell signaling, metabolism, and cancer genetics in the Duke Cancer Institute (DCI).

The programmatic mission and scope of the CB program is to collectively foster current and seed future basic research in cancer cell signaling and cancer genetics in order to promote foundational advancements in cancer biology. CB supports this theme through three aims: 1) foster high-impact, basic research in cancer cell signaling and cancer genetics; 2) promote transdisciplinary research in these fields; and 3) train the next generation of basic cancer researchers.

Focus Areas

Focus Area 1 – Cancer Cell Signaling: signal transduction, metabolism, stem cells, tumor microenvironment

Focus Area 2 – Cancer Genetics: recombination/replication/repair; gene regulation and epigenetics; RNA biology; structural biology; genomics; viral oncology; microbiome

Leadership Bios

Anne Marie Pendergast, PhD: The focus of the research in the Pendergast Lab is to investigate the role of tyrosine kinase-dependent transcription factor networks during tumor metastasis as well as the regeneration response following lung injury. In particular, one area of current research is to dissect the pathways that modulate the tumor-neural cell crosstalk during metastasis to the brain using animal models and state-of-the art transcriptomic technologies. Dr. Pendergast is the Anthony R. Means Cancer Biology Professor, Vice Chair of Pharmacology and Cancer Biology, and Director of Graduate Studies in Molecular Cancer Biology at Duke University. She is also co-leader of the Cancer Biology Program at the Duke Cancer Institute. Dr. Pendergast has extensive experience in training and mentoring students, postdoctoral fellows and junior faculty. Dr. Pendergast has served as a member of multiple NIH study sections and served in the NCI Board of Scientific Counselors.

Jen-Tsan "Ashley" Chi, MD, PhD: Chi lab has been using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on three areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, via novel mechanisms. Third, we also perform genomic study of erythrocyte transcriptomes in the contexts of human diseases, blood storage, and malaria infection.

Micah Luftig, PhD: The focus of research in the Luftig laboratory is aimed at understanding how the common herpesvirus, Epstein-Barr virus (EBV), causes cancer. Virtually all adults are latently infected with EBV. However, this virus is associated with nearly 200,000 cancer deaths annually including lymphoid and epithelial malignancies. The laboratory focuses on the molecular basis for EBV-mediated tumorigenesis primarily focused on the B cell transformation model. Recently, the laboratory has developed several translational collaborations aimed at defining and characterizing the mechanisms underpinning new therapeutic strategies for EBV-positive cancers. Dr. Luftig is currently the Vice Chair of the Department of Molecular Genetics and Microbiology (MGM) and the Director of the Duke Center for Virology as well as the PI of a long-standing NCI-supported T32 Training Program in Viral Oncology.

Centers and Labs

The Pendergast Lab: The long-term goal of the research in the Pendergast laboratory is to define the pathways that integrate activation of diverse growth factor, chemokine and adhesion receptors to the regulation of cell polarity, migration, and invasion during normal development and cancer, with emphasis on the role of the Abl family of non-receptor tyrosine kinases and their targets.

The Jen-Tsan Ashley Chi, MD, PhD Lab: We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but with some very interesting twists and novel mechanisms.

The Luftig Lab: Our laboratory focuses on the mechanisms by which Epstein-Barr virus activates and ultimately subverts the host oncogenic stress response to growth transform primary B lymphocytes into indefinitely proliferating lymphoblastoid cell lines (LCLs). EBV infection of B cells leads to a latent growth program where eight viral proteins and several non-coding RNAs are expressed.

Graduate Training Programs in Pharmacology and Cancer Biology:

Pharmacological Sciences Training Program: The Pharmacological Sciences Training Program (PSTP) is an interdisciplinary training program administered in the Department of Pharmacology and Cancer Biology that provides an integrated training experience in Pharmacology for students in the biomedical sciences. The Program recruits students from all biomedical science departments who are interested in broadening their training through instruction in Pharmacology and related disciplines. The program provides funds for stipend, tuition and fees for two years of graduate training and supports travel to national meetings during the period of support. Pharmacology provides a strong foundation for future employment both in academia and in industry, and our graduates tell us that the instruction in this basic discipline proved to be one of the most useful components of the PhD training at Duke University.

Molecular Cancer Biology Program: Molecular cancer biologists at Duke University seek to understand the complex regulatory mechanisms that govern mammalian cell growth and differentiation, discern how these mechanisms are perturbed in malignant cells, and how our knowledge of these regulatory mechanisms might lead to improved anti-cancer therapy. This research covers the boundaries of disciplines such as pharmacology, biochemistry, molecular biology, genetics, genomics, and cell biology, which together are leading to greater understanding of the basic mechanisms underlying growth regulation and their alterations during tumor progression and metastasis.

Molecular Genetics and Microbiology Graduate Program: The Duke Molecular Genetics and Microbiology Graduate Program along with The Graduate School is dedicated to and benefits from a student population diverse in background, culture, socioeconomic status, race, ethnicity, and work and life experiences that contribute to a fuller representation of perspectives within the academic life of the university. In addition, within the Biomedical Graduate Programs in the School of Medicine and School of Nursing, we have an Office of Biomedical Graduate Education (OBGE) that provides signature programming for students within our program.

Virology Oncology Training Grant: The purpose of the Viral Oncology Research Training Program is to provide training at the pre- and postdoctoral levels in the general field of molecular virology with an emphasis on the molecular biology of tumor viruses and oncogenes. Seventeen faculty members in various academic departments at Duke University Medical Center, working in the areas of molecular virology, viral and molecular oncology, and viral vector-based cancer vaccine therapeutics, constitute the program faculty. These faculty members train graduate students and postdoctoral fellows who are supported by a variety of mechanisms including institutional research training programs, research grants, and individual pre- and postdoctoral fellowships.

Scientific Highlights

Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. Here, we report on the discovery of an actionable signaling pathway utilized by metastatic tumor cells whereby the transcriptional regulator Heat Shock Factor 1 (HSF1) drives a transcriptional program, divergent from its canonical role as the master regulator of the heat shock response, leading to enhanced expression of a subset of E2F transcription factor family gene targets.

Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis.
Lymphoblastoid cell lines (LCLs) are generated by transforming primary B cells with Epstein-Barr virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution.
The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis.

Clinical Trials