This application seeks the mechanisms underlying the roles of YAP/TAZ in cancer. A wide variety of human cancers have altered YAP/TAZ signaling that is generally connected to prognosis. YAP and its cousin TAZ are the major effectors of Hippo pathway that controls organ size, cell movement, proliferation and survival. This pathway also regulates other important signaling pathways (Hedgehog, Notch, TGF? and Wnt). We will use murine polyomavirus (MuPyV) to probe YAP function. MuPyV causes a broad range of tumors. Its study has illuminated the roles of tyrosine phosphorylation and PI3 kinase in cancer. It continues to point to important issues, such as the role of PP2A A? isoform, in cancer. Recently, we reported that MuPyV's small T antigen (ST) directly binds YAP and alters its phosphorylation, stability, and function by promoting its association with PP2A. This interaction allows ST to block differentiation in several systems. Extensive preliminary data on MT, the oncogene of MuPyV, show that MT also associates with YAP. This association is important for MT driven neoplastic transformation. MT also affects YAP phosphorylation, but MT's effects are different than those of ST.
Our first aim i s to study ST regulation of the differentiation of stem-like cells. Since we know that ST also interacts with TAZ, we will test whether it contributes to the phenotype.
This aim will include a determination of the transcriptional mechanisms involved and the YAP effector protein associations that ST uses to achieve these alterations.
Our second aim will be to study the roles of YAP in MT driven transformation. Here too we will be interested in changes in gene expression and protein-protein associations. In our last aim we seek to examine the roles of YAP in MuPyV MT mediated transformation in vivo using transgenic and knockout mice. In the context of this Program Project, we have a great opportunity to exploit the virus interactions to gain a deeper insight into Hippo signaling in human oncogenesis. By comparing our results on the effects of MuPyV ST/MT on PP2A/YAP/TAZ with the results of our colleagues working with SV40 ST and Merkel ST and those of the Hahn lab working on YAP in K-Ras driven human cancers, we should be able to determine which of YAP's effects on cellular signaling are truly important, greatly enhancing the impact of our data. Ideally, these studies will lead us to our ultimate goal of translating our work into human cancer therapy, as we have previously done for PI3 kinase.

Public Health Relevance

The polyoma virus ST/MT antigens regulate YAP phosphorylation, stability and function by altering its interaction with PP2A. Notably these YAP/TAZ/PP2A interaction are essential for oncogenesis. This grant will determine the mechanisms linking viral oncogenesis via PP2A/YAP/TAZ and human cancer to improve therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA203655-01A1
Application #
9358180
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Tarnita, Roxana M; Wilkie, Adrian R; DeCaprio, James A (2018) Contribution of DNA replication to the FAM111A-mediated simian virus 40 host range phenotype. J Virol :
Becker, J├╝rgen C; Stang, Andreas; DeCaprio, James A et al. (2017) Merkel cell carcinoma. Nat Rev Dis Primers 3:17077
Zhang, Jing; Gao, Xueliang; Schmit, Fabienne et al. (2017) CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep 20:549-557
Cheng, Jingwei; Park, Donglim Esther; Berrios, Christian et al. (2017) Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis. PLoS Pathog 13:e1006668
Kang, Un-Beom; Alexander, William M; Marto, Jarrod A (2017) Interrogating the hidden phosphoproteome. Proteomics 17:
Ni, Jing; Xie, Shaozhen; Ramkissoon, Shakti H et al. (2017) Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol 19:22-30
Tsherniak, Aviad; Vazquez, Francisca; Montgomery, Phil G et al. (2017) Defining a Cancer Dependency Map. Cell 170:564-576.e16
Hsu, Jessie Hao-Ru; Hubbell-Engler, Benjamin; Adelmant, Guillaume et al. (2017) PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer. Cancer Res 77:4613-4625
Rouleau, Cecile; Pores Fernando, Arun T; Hwang, Justin H et al. (2016) Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP. J Virol 90:7032-7045
Odajima, Junko; Saini, Siddharth; Jung, Piotr et al. (2016) Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo. PLoS Genet 12:e1006429