This grant describes experiments in which we'll continue to develop the Sleeping Beauty (SB), and other transposons, as tools for uncovering important aspects of cancer genetics. The main innovations we've developed over the past grant period are tissue-specific methods for transposon mutagenesis and new methods for large-scale cloning and analysis of transposon insertion sites. During the new budget period we will develop a new innovation in this field of research. We will use transposon mutagenesis to study the evolution of metastases in autochthonous models of cancer in mice. This renewal application is focused on the biology of osteosarcoma (OS). Transposon-based mouse models for this tumor were developed during the last budget period. We expect to generate new insights into the genetic changes that can initiate and can cause progression of this devastating pediatric cancer. In addition, our work will address when, where and how the metastatic subclone evolves from primary OS in an autochthonous mouse model of OS. Therefore, we have developed important collaborative relationships with scientists engaged in the genomic analysis human and canine OS. An important aspect of this proposal is the comparative genetic analysis of human, canine and murine OS. Finally, we describe collaborative experiments with an expert in the field of sarcoma metastasis.
This grant describes experiments in which new technologies in cancer genetics will be developed to study the process of sarcoma development and its spread to distant parts of the body. These are processes that are poorly understood. The project is focused on an important form of childhood cancer called osteosarcoma.
|Abbott, Kenneth L; Nyre, Erik T; Abrahante, Juan et al. (2015) The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice. Nucleic Acids Res 43:D844-8|
|Tschida, Barbara R; Largaespada, David A; Keng, Vincent W (2014) Mouse models of cancer: Sleeping Beauty transposons for insertional mutagenesis screens and reverse genetic studies. Semin Cell Dev Biol 27:86-95|
|Moriarity, Branden S; Rahrmann, Eric P; Beckmann, Dominic A et al. (2014) Simple and efficient methods for enrichment and isolation of endonuclease modified cells. PLoS One 9:e96114|
|Watson, Adrienne L; Anderson, Leah K; Greeley, Andrew D et al. (2014) Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget 5:1502-14|
|Moriarity, Branden S; Rahrmann, Eric P; Keng, Vincent W et al. (2013) Modular assembly of transposon integratable multigene vectors using RecWay assembly. Nucleic Acids Res 41:e92|
|Keng, Vincent W; Sia, Daniela; Sarver, Aaron L et al. (2013) Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. Hepatology 57:120-30|
|Bergemann, Tracy L; Starr, Timothy K; Yu, Haoyu et al. (2012) New methods for finding common insertion sites and co-occurring common insertion sites in transposon- and virus-based genetic screens. Nucleic Acids Res 40:3822-33|
|Starr, Timothy K; Scott, Patricia M; Marsh, Benjamin M et al. (2011) A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis. Proc Natl Acad Sci U S A 108:5765-70|
|Bender, Aaron M; Collier, Lara S; Rodriguez, Fausto J et al. (2010) Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas. Cancer Res 70:3557-65|
|Hackett, Perry B; Largaespada, David A; Cooper, Laurence J N (2010) A transposon and transposase system for human application. Mol Ther 18:674-83|
Showing the most recent 10 out of 22 publications