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.
|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|
|Morrissy, A Sorana; Garzia, Livia; Shih, David J H et al. (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529:351-7|
|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|
|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|
|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|
|Moriarity, Branden S; Otto, George M; Rahrmann, Eric P et al. (2015) A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat Genet 47:615-24|
|Mirabello, Lisa; Koster, Roelof; Moriarity, Branden S et al. (2015) A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma. Cancer Discov 5:920-31|
|Dorr, Casey; Janik, Callie; Weg, Madison et al. (2015) Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor. Mol Cancer Res 13:1238-47|
|Zuckermann, Marc; Hovestadt, Volker; Knobbe-Thomsen, Christiane B et al. (2015) Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat Commun 6:7391|
|Moriarity, Branden S; Largaespada, David A (2015) Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery. Curr Opin Genet Dev 30:66-72|
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