There are seven known cancer viruses, two of which (Kaposi's sarcoma herpesvirus, KSHV/HHV8, and Merkel cell polyomavirus, MCV) were discovered by my laboratory. This R35 application will consolidate currently funded research in my laboratory and provide resources to complete currently unfunded research. It focuses on three main areas: 1) Merkel cell polyomavirus-related cancer and oncogenesis: MCV is the first polyomavirus known to cause human cancer. We are investigating the basic mechanisms used by this virus to regulate cap-dependent translation, to modulate cellular signaling pathways and to dysregulate the cell cycle. Our findings have direct relevance to Merkel cell carcinoma (MCC) but also apply to other noninfectious cancers as well. Ongoing NCI funding on this topic will be incorporated into the R35 award. 2) The role of oncoprotein translation variability in KSHV oncogenesis: We find that LANA1 undergoes a unique form of previously undescribed repeat +1 frameshifting at internal repeat sequences. This reveals that the major oncogene for KSHV expresses previously unknown proteins that could contribute to cell proliferation. Understanding the molecular mechanism for this frameshifting may have relevance to neurodegenerative diseases caused by cellular gene frameshift recoding through a similar mechanism. 3) New ways to find new human cancer viruses: We developed digital transcriptomic subtraction to discover MCV in MCC. Combining transcriptome information with proteomic analyses is a promising approach to discovering additional new agents. This may be particularly important for persistent viral infections in which viral proteins have reduced turnover to prevent host immune recognition. Under these circumstances, viral RNA levels can be miniscule - limiting the ability to detect the agent - while highly stable viral proteins may be abundant. This proposal supports both basic and translational research on new ways that viruses can induce human cancers. I anticipate that it will lay a basis for new insights into methods to reliably determine the role of viruses in human cancers and to uncover novel common cancer pathways that are at work in both infectious and noninfectious tumors.

Public Health Relevance

The Outstanding Investigator Award (R35, PAR-14-267) seeks to provide resources to successful, funded investigators so that novel, high-risk/high-reward and long-term cancer research initiatives can be undertaken. My laboratory, in collaboration with Dr. Yuan Chang, discovered the virus that causes Kaposi sarcoma, the most common cancer among AIDS patients, and another virus that causes Merkel cell carcinoma, the most severe form of skin cancer. We have exploited each of these discoveries to uncover new mechanisms for cancer development, new diagnostics and new therapeutic and preventive options. My group has been continuously NCI funded for nearly 20 years and this R35 award will consolidate two R01 grants on which I am the principle investigator. My work has been cited nearly 20,000 times and is recognized by international honors, including the Charles S. Mott Prize and the Robert Koch Prize. I am an elected member of the National Academy of Sciences and I have been awarded an American Cancer Society Professorship. During the course of this grant, we will work to uncover new cancer causing pathways used by these viruses that may have general importance cancer cell proliferation. We will also develop a long-term initiative to identify viral peptides de novo, in combination with digital transcriptome subtraction, to identify new infectious causes for human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197463-02
Application #
9240607
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2016-03-08
Project End
2023-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$830,317
Indirect Cost
$290,317
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kwun, Hyun Jin; Chang, Yuan; Moore, Patrick S (2017) Protein-mediated viral latency is a novel mechanism for Merkel cell polyomavirus persistence. Proc Natl Acad Sci U S A 114:E4040-E4047
Kwun, H J; Wendzicki, J A; Shuda, Y et al. (2017) Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting. Oncogene 36:6784-6792
Chang, Yuan; Moore, Patrick S; Weiss, Robin A (2017) Human oncogenic viruses: nature and discovery. Philos Trans R Soc Lond B Biol Sci 372:
Moore, Patrick S; Chang, Yuan (2017) Common Commensal Cancer Viruses. PLoS Pathog 13:e1006078
Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro et al. (2016) Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. Proc Natl Acad Sci U S A 113:8466-71
Toptan, Tuna; Yousem, Samuel A; Ho, Jonhan et al. (2016) Survey for human polyomaviruses in cancer. JCI Insight 1: