Merkel cell carcinoma (MCC) has two distinct etiologies: one due to integration of Merkel cell polyomavirus (MCPyV) DNA with sustained expression of Large T antigen (LT) and Small T antigen (ST) and the other due to excessive sunlight/UV induced damage to the tumor genome. The overall hypothesis of this proposal is that the two distinct forms of MCC perturb similar signaling pathways either disrupted by UV-induced mutations in virus-negative MCC or functionally perturbed by the MCPyV T antigens in virus-positive MCC. We propose that in addition to inactivation of RB and p53 function, MCPyV T antigens serve to functionally inactivate Notch, BAF and other developmentally regulated signaling pathways that contribute to oncogenesis. Our laboratory has determined that MCPyV ST recruits the MYC homolog MYCL (also known as L-Myc) to the EP400 (Tip60, NuA4) complex to transactivate specific gene expression. We have evidence that the ST- MYCL-EP400 complex activates several components of the CoREST complex including LSD1 (KDM1A), RCOR2 and INSM1 and that the lysine demethylase activity of LSD1 is required for the viability and proliferation of virus-positive MCC cell lines. We will test the overall hypothesis that the ST-MYCL-EP400 and CoREST-LSD1 complexes are required for MCPyV ST dependent oncogenesis in MCC and function, at least in part, to inhibit Notch and BAF activity. To test this hypothesis, we will perform the following Aims.
In Specific Aim 1, we will determine the contribution of MYCL and the EP400 complex to ST transformation. We will generate dominant negative versions of MYCL and the EP400 complex and determine if they can disrupt ST transforming activity. We will determine if additional MYCL binding proteins contribute to ST mediated transformation. We will determine how broadly applicable our model for the oncogenic role of the ST-MYCL-EP400 complex in a variety of newly established MCC cell lines.
In Specific Aim 2, we will determine the role of the CoREST-LSD1 complex in MCPyV ST transformation. We will identify CoREST-LSD1 dependent target genes in virus-positive MCC and determine the dependency of ST mediated transformation on the CoREST-LSD1 complex in normal cells.
In Specific Aim 3, we will determine the role of Notch signaling in VP-MCC. We will identify the target genes that are repressed by ST and the CoREST-LSD1 complex and determine if expression of these genes reduces viability and proliferation. We will determine the tumor suppressor role of a recently identified SWI/SNF BAF complex in promoting Notch signaling in VP-MCC. Successful completion of the proposed aims will bring significant new insights into MCPyV and viral oncogenesis. In addition, this proposal seeks to gain insight into how perturbations in the epigenetic regulation of development pathways contributes to MCC. The experiments proposed will identify and validate several new pathways required for MCC oncogenesis that can be developed for new targeted therapeutics.

Public Health Relevance

Merkel cell carcinoma is caused by the integration of Merkel cell polyomavirus (MCPyV) DNA and sustained expression of Large T antigen (LT) and Small T antigen (ST). Our laboratory has determined that MCPyV ST recruits the MYC homolog MYCL (also known as L-Myc) to the EP400 (Tip60, NuA4) complex to transactivate the CoREST-LSD1 complex in Merkel cell carcinoma. The experiments proposed will identify new pathways required for Merkel cell carcinoma that can be developed to identify new targeted therapeutics for the improved treatment of this highly aggressive cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA173023-06A1
Application #
9660123
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2013-07-01
Project End
2023-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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