In this proposal Dr. Starr will use Sleeping Beauty (SB) transposon-based mutagenesis to screen fornovel cancer genes. The protein products of identified genes will be analyzed for their role in human cancer byaltering their levels in cell lines and measuring the effect on proliferation, apoptosis, colony formation, andsignaling pathways. The SB system has been used to drive tumorigenesis in mice and subsequently identifyboth known and novel genetic mutations that drive leukemias, sarcomas, hepatocellular carcinomas, andcolorectal cancers. Some tissue types, however, have proven refractory to SB mutagenesis. To successfullyscreen for genes in these tissues Dr. Starr has proposed several modifications to the SB system. Dr. Starr has been instrumental in developing the SB system during his tenure as a post-doctoral fellowin the Masonic Cancer Center (MCC) at the University of Minnesota. To help Dr. Starr transition to anindependent research career, he has assembled an advisory committee consisting of experts in severaldifferent areas critical for the success of his research and career development. In addition to the direct supportprovided by his Mentor and advisory committee, Dr. Starr will use the shared resources available in the MCC.These include core facilities in biological imaging, tissue procurement, flow cytometry, comparative pathology,cytogenetics, bioinformatics/biostatistics, RNA interference, high-throughput sequencing, and a MouseGenetics Laboratory capable of generating transgenic, knock-out, and knock-in mice. The candidate intends tocontinue his post-doctoral fellowship for two years while working on Aims 1 and 2 of this research proposal.Dr. Starr's long-term goal is to secure a position as an independent investigator in an academic setting wherehe plans on dedicating his career to understanding the genetic mechanisms driving cancer. Studies documenting genetic changes within human tumor genomes confirm that a large number ofgenetic defects contribute to tumor growth, yet only a small subset have been characterized. Furthermore,within a single tumor type there is great heterogeneity between individual tumors. The studies in this proposaladdress a critical need in the field of cancer research to develop better methods of identifying the subset ofgenetic changes that are actually driving tumor growth.
In Specific Aims 1 and 2, several novel candidatecancer-driving genes identified by Dr. Starr in a screen for colorectal cancer (Wac, Tcf12, and Rspo2) and lungcancer (Akap13, Cul3, and Map4k3) will be studied to determine their specific role in human cancer. Thelevels of these proteins will be altered in human cell lines, both normal and transformed, to determine theireffect on growth, apoptosis, the ability to form colonies in soft agar, and regulation of key signaling pathways.
Aim 3 proposes several improvements to the SB system, using newly developed highly active transposasesand transposons, to uncover novel lung cancer genes. The results of these studies can be used to develop amore personalized approach to cancer therapy.

Public Health Relevance

The goal of this project is to use an animal model to understand the genetic basis of lung and colorectal cancer. The genetic mutations discovered using this animal model will then be functionally tested in human lung and colorectal cancer tissue and cell lines. The results of these studies will help us decide how to better treat these common, deadly cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA151672-02
Application #
8281731
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mietz, Judy
Project Start
2011-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$241,529
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Clark, Christopher R; Maile, Makayla; Blaney, Patrick et al. (2018) Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene. Sci Rep 8:15327
Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar et al. (2018) Corrigendum to ""Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells"" [Gyncol. Oncol. 144 (2017) 598-606]. Gynecol Oncol 151:182-186
Morris, Shelli M; Davison, Jerry; Carter, Kelly T et al. (2017) Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms. Int J Cancer 140:853-863
Zhao, Xianda; Li, Lihua; Starr, Timothy K et al. (2017) Tumor location impacts immune response in mouse models of colon cancer. Oncotarget 8:54775-54787
Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar et al. (2017) Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells. Gynecol Oncol 144:598-606
Heltemes-Harris, L M; Larson, J D; Starr, T K et al. (2016) Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B-cell acute lymphoblastic leukemia. Oncogene 35:3454-64
Anderson, Sarah; Poudel, Kumud Raj; Roh-Johnson, Minna et al. (2016) MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation. Proc Natl Acad Sci U S A 113:E5481-90
Ho, Yen-Yi; Starr, Timothy K; LaRue, Rebecca S et al. (2016) Case-oriented pathways analysis in pancreatic adenocarcinoma using data from a sleeping beauty transposon mutagenesis screen. BMC Med Genomics 9:16
Clark, Christopher R; Starr, Timothy K (2016) Mouse models for the discovery of colorectal cancer driver genes. World J Gastroenterol 22:815-22
Than, B L N; Linnekamp, J F; Starr, T K et al. (2016) CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 35:4179-87

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