- PROJECT 2 The central goal of Project 2 is to understand the various roles of alternative splicing in cancer, and to exploit cancer-specific features of this process to develop targeted-therapeutic approaches. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the numerous isoforms that are inappropriately expressed contribute to tumorigenesis or altered cell metabolism. The mechanisms and pathways through which the splicing-factor oncoproteins SRSF2 and SRSF1 transform cells will continue to be investigated. Cell-culture models, as well as orthotopic and genetic mouse models will be used to study tumorigenesis promoted by these splicing factors upon mutation or overexpression in different cancer contexts, with an emphasis on recurrent mutations in myeloid dysplasias. High-throughput RNA-sequencing and computational analysis will be employed to identify and compare the splicing targets of these SR proteins in different cancer contexts, and selected targets will be characterized and manipulated to evaluate their contributions to tumorigenesis and potential as therapeutic targets or biomarkers. One key event, alternative splicing of pyruvate kinase pre-mRNA, which controls the distinctive glycolytic metabolism of cancer cells, will be thoroughly investigated as a potential therapeutic target, by specifically manipulating this process in vivo, using antisense technology and mouse models of glioma and hepatocellular carcinoma.

Public Health Relevance

- PROJECT 2 Alternative splicing is a fundamental step in the normal function of genes. In cancer cells, this process is altered in ways that can contribute to tumor growth. By studying the roles of alternative splicing in cancer, unique vulnerabilities of cancer cells can be uncovered, which can then be investigated as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA013106-46A1
Application #
9417198
Study Section
Special Emphasis Panel (ZCA1)
Project Start
1997-02-10
Project End
2023-01-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
46
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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