Project 3: Dissecting p53 Action in a Mouse Lymphoma Model Scott Lowe, Ph.D. p53 is a potent tumor suppressor that limits cancer development and contributes to the anti-tumor effects of certain cytotoxic agents. Accordingly, p53 mutations are associated with aggressive cancers, poor patient prognosis and, in some cases, therapy resistance. Our project studies the p53 network using the Ep-myc transgenic mouse, a well characterized model of B cell lymphoma in which p53 profoundly impacts tumorigenesis and treatment outcome. We previously used the E?mu?-myc system to study how p53 loss promotes tumor development and drug resistance, and to explore the relationship between cancer genotype, tumor progression, tumor maintenance, and treatment sensitivity. These studies produced new insights into p53 regulation and effector mechanisms in diverse contexts where it limits proliferation. They also established that p53 loss is required for tumor maintenance and that translational control of cell survival is a druggable mediator of oncogenesis. To facilitate our goals, we developed methods to genetically manipulate E?mu?-myc lymphomas, enabling the rapid and cost-effective production of mice harboring tumors with diverse genotypes. We also incorporated small animal imaging methods to track lymphoma progression and response, and stable and inducible RNAi technology to fine tune and study loss of function phenotypes. Moving forward, we seek to further explore the interplay between cancer genetics and cancer therapy in the E?mu?-myc system in order to produce a more complete picture of the p53 network and its action in vivo. We also wish to understand in detail how p53 mutations impact tumor behavior, and identify new therapeutic targets based on the vulnerabilities they create. We will perform focused RNAi screens to identify new modulators of p53 action relevant to suppressing tumorigenesis and/or modulating therapy response, test the hypothesis that the deletions on chromosome 17p influence cancer biology beyond simply inactivating p53, and identify and characterize drug targets that interact with the p53 tumor suppressor network. Our approach uses genomic data from human lymphoma to inform function studies in mice, and implements a suite of new animal modeling and genetic tools that are time and cost effective.

Public Health Relevance

Successful completion of these studies will functionalize genetic changes that occur in human lymphoma and determine how they impact p53 action and/or influence disease behavior. They may also identify new therapeutic targets for treating p53 mutant cancers, which are often aggressive and more refractory to conventional therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087497-13
Application #
8566829
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2013
Total Cost
$390,249
Indirect Cost
$73,705
Name
Columbia University (N.Y.)
Department
Type
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Castillo-Martin, Mireia; Collazo Lorduy, Ana; Gladoun, Nataliya et al. (2016) H-RAS mutation is a key molecular feature of pediatric urothelial bladder cancer. A detailed report of three cases. J Pediatr Urol 12:91.e1-7
Torrano, Veronica; Valcarcel-Jimenez, Lorea; Cortazar, Ana Rosa et al. (2016) The metabolic co-regulator PGC1α suppresses prostate cancer metastasis. Nat Cell Biol 18:645-56
Yoh, Kathryn E; Regunath, Kausik; Guzman, Asja et al. (2016) Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells. Proc Natl Acad Sci U S A 113:E6107-E6116
Levine, Arnold J; Ting, David T; Greenbaum, Benjamin D (2016) P53 and the defenses against genome instability caused by transposons and repetitive elements. Bioessays 38:508-13
Vidal, Samuel J; Rodriguez-Bravo, Veronica; Quinn, S Aidan et al. (2015) A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell 27:223-39
Zhao, Zhen; Chen, Chi-Chao; Rillahan, Cory D et al. (2015) Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet 47:539-43
Danielson, Laura S; Reavie, Linsey; Coussens, Marc et al. (2015) Limited miR-17-92 overexpression drives hematologic malignancies. Leuk Res 39:335-41
Epping, M T; Lunardi, A; Nachmani, D et al. (2015) TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation. Cell Death Differ 22:1353-62
Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2015) PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. Cancer Med 4:1258-71
Chakraborty, A A; Scuoppo, C; Dey, S et al. (2015) A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34:2406-9

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