Project 5: S. Lowe Tumor Suppression Hannon, Gregory J PROJECT SUMMARV (See instructions): This project studies tumor-suppressor gene (TSG) networks and how their disruption influences malignant behavior. Initially based on its observation that oncogenes can activate p53 to promote apoptosis, our early efforts involved studying mechanisms whereby p53 drives apoptosis and how suppression of p53 effectors or deregulated survival signaling can circumvent during promote tumorigenesis. Over the last funding cycle, we identified several new regulators of oncogene-induced apoptosis that contribute to tumorigenesis and validated translational control of cell survival as a therapeutic target. Taking advantage of inducible RNAi technology we developed with Greg Hannon, we also showed that reactivation of endogenous p53 in tumors potently triggered apoptosis or senescence depending on context, thus establishing a role for p53 loss in tumor maintenance. Finally, exploiting unique features of the mouse models developed in the program we, through candidate gene testing and in vivo screens, identified and validated several new oncogenes and over 35 new TSGs that are relevant to human cancer. Moving forward, the project will continue to innovate at both the biological and technical levels, taking a more comprehensive approach towards studying tumor suppressors, with a particular focus on their action in gastrointestinal malignancies and an eye towards developing new therapeutic targets. Specifically, we will identify and characterize new TSGs in several gastrointestinal malignancies, study the role of extremely common but poorly understood large chromosomal deletions on cancer development, explore the action of key TSGs in tumor maintenance, and perform negative selection RNAi screens to identify and then characterize potential vulnerabilities created by TSG loss. Experimentally, we will take advantage of genomic analyses of human gastrointestinal cancers to inform functional studies in mice, and implement a suite of new RNAi tools and animal modeling approaches to increase the cost effectiveness and pace of our analyses. Successful completion of these studies will identify new genes relevant to human gastrointestinal malignancies and determine how they influence disease behavior. Our efforts may also identify new therapeutic targets for treating cancers with TSG mutations, which have otherwise been difficult to exploit therapeutically. In addressing these aims, our project will produce a blueprint that can be applied to other genes and tumor types. Our goal is to gain a more comprehensive understanding of tumor suppressor networks and identify therapeutic targets relevant to specific cancer genotypes.

Public Health Relevance

Our project illustrates a comprehensive approach toward identifying and characterizing tumor suppressor and tumor maintenance genes. Its successful completion will identify new TSGs of direct relevance to human gastrointestinal cancers, provide insights into the action of large chromosomal deletions on tumorigenesis, and identify new therapeutic targets for tumors with TSG mutations, whose inactivation has previously been difficult to exploit.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Cold Spring Harbor Laboratory
Cold Spring Harbor
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Diermeier, Sarah D; Chang, Kung-Chi; Freier, Susan M et al. (2016) Mammary Tumor-Associated RNAs Impact Tumor Cell Proliferation, Invasion, and Migration. Cell Rep 17:261-74
O'Rourke, Kevin P; Dow, Lukas E; Lowe, Scott W (2016) Immunofluorescent Staining of Mouse Intestinal Stem Cells. Bio Protoc 6:
Anczuków, Olga; Krainer, Adrian R (2016) Splicing-factor alterations in cancers. RNA 22:1285-301
Tschaharganeh, Darjus F; Lowe, Scott W; Garippa, Ralph J et al. (2016) Using CRISPR/Cas to study gene function and model disease in vivo. FEBS J 283:3194-203
Hossain, Manzar; Stillman, Bruce (2016) Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. Elife 5:
Arun, Gayatri; Diermeier, Sarah; Akerman, Martin et al. (2016) Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 30:34-51
Tschaharganeh, Darjus F; Xue, Wen; Calvisi, Diego F et al. (2016) p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer. Cell 165:1546-1547
O'Rourke, Kevin P; Ackerman, Sarah; Dow, Lukas E et al. (2016) Isolation, Culture, and Maintenance of Mouse Intestinal Stem Cells. Bio Protoc 6:
Tschaharganeh, Darjus F; Bosbach, Benedikt; Lowe, Scott W (2016) Coordinated Tumor Suppression by Chromosome 8p. Cancer Cell 29:617-9
Guo, Ya; Xu, Quan; Canzio, Daniele et al. (2015) CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function. Cell 162:900-10

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