University of Pittsburgh Cancer Institute (UPCI)

Viral Oncology (VO)

Human PapillomavirusThis group of scientists performs cutting-edge research at the forefront of some of the most exciting areas of cancer biology. Viruses have long been used as tools to understand basic mechanisms of cancer development and progression. Many cellular proteins crucial in oncogenesis and tumor suppression were first discovered by studying tumor viruses. UPCI is building on this foundation and has gathered an extremely strong and interactive group of tumor virologists who use viruses to understand how cancers arise or progress. Although members of this interest area use traditional approaches to investigate viral interactions with cancer cell signaling pathways, VO faculty members are also building approaches to understanding virus-host cell interactions in areas such as microRNA (miRNA) perturbations, innate immune evasion, and genomic instability caused by viruses.

Selected Publications

  • Virus infection is sensed in the cytoplasm by retinoic acid-inducible gene I (RIG-I), which requires RNA and polyubiquitin binding to induce type I interferon (IFN) and activate cellular innate immunity. CVP members discovered a mechanism by which the IFN-inducible oligoadenylate synthetases-like (OASL) protein contributes to host antiviral responses by enhancing RIG-I activation. (Zhu et. al., Immunity. 2014 Jun 19;40(6):936-48.)
  • Polyomaviruses encode a large T Ag (LT), a multifunctional protein essential for the regulation of both viral and host cell gene expression and productive viral infection. Results show that, in the absence of viral infection, LT-initiated activation of ataxia-telangiectasia mutated and Rad3-related (ATR) kinase-dependent DNA damage response is sufficient for the induction of an IFN-β-mediated innate immune response in human cells. Thus, a novel and critical role for ATR was uncovered, as a mediator of antiviral responses utilizing LT. (Forero et. al., J Immunol. 2014 Jun 15;192(12):5933-42.)
  • Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ~80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. Studies have now confirmed that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels, and significantly improved mouse survival for 3 of 4 MCV-positive MCC xenografts. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs. (Dresang et. al., PLoS One. 2013 Nov 18;8(11):e80543.)
  • MCV causes an aggressive human skin cancer, MCC, through expression of small T (sT) and large T (LT) viral oncoproteins. MCV sT is also required for efficient MCV DNA replication by the multifunctional MCV LT helicase protein. It was discovered that LT is targeted for proteasomal degradation by the cellular SCF(Fbw7) E3 ligase, which can be inhibited by sT through its LT-stabilization domain (LSD). Consequently, sT also stabilizes cellular SCF(Fbw7) targets, including the cell-cycle regulators c-Myc and cyclin E. Mutating the sT LSD decreases LT protein levels and eliminates synergism in MCV DNA replication as well as sT-induced cell transformation. SCF(Fbw7) knockdown mimics sT-mediated stabilization of LT, but this knockdown is insufficient to fully reconstitute the transforming activity of a mutant LSD sT protein. Thus, MCV has evolved a regulatory system involving SCF(Fbw7) that controls viral replication but also contributes to host cell transformation. (Kwun et. al., Cell Host Microbe. 2013 Aug 14;14(2):125-35.)

Members

Section Leader: Saumendra Sarkar, PhD

Chang, Yuan, MD
Pathology
Moore, Patrick, MD, MPH
Microbiology and Molecular Genetics
Conway, James, PhD
Structural Biology
Pipas, James, PhD
Biological Sciences
Coyne, Carolyn, PhD
Microbiology and Molecular Genetics
Sarkar, Saumendra, PhD
Microbiology and Molecular Genetics
Homa, Fred, PhD
Microbiology and Molecular Genetics
Shair, Kathy, PhD
Microbiology and Molecular Genetics
Khan, Saleem, PhD
Microbiology and Molecular Genetics
Smithgall, Thomas, PhD
Microbiology and Molecular Genetics
Kinchington, Paul, PhD
Ophthalmology
Xiao, Gutian, PhD
Microbiology and Molecular Genetics
Metes, Diana, MD
Surgery