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.
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|Scott, Milcah C; Temiz, Nuri A; Sarver, Anne E et al. (2018) Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma. Cancer Res 78:326-337|
|Kawakami, Koichi; Largaespada, David A; Ivics, Zoltán (2017) Transposons As Tools for Functional Genomics in Vertebrate Models. Trends Genet 33:784-801|
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|Shu, Jingmin; Li, Lihua; Sarver, Anne E et al. (2016) Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma. Oncotarget 7:21298-314|
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|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|
|Marko, Tracy A; Shamsan, Ghaidan A; Edwards, Elizabeth N et al. (2016) Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma. Sci Rep 6:39059|
|Temiz, Nuri A; Moriarity, Branden S; Wolf, Natalie K et al. (2016) RNA sequencing of Sleeping Beauty transposon-induced tumors detects transposon-RNA fusions in forward genetic cancer screens. Genome Res 26:119-29|
|Wu, Jianqiang; Keng, Vincent W; Patmore, Deanna M et al. (2016) Insertional Mutagenesis Identifies a STAT3/Arid1b/?-catenin Pathway Driving Neurofibroma Initiation. Cell Rep 14:1979-90|
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