Molecular Basis of Aneuploidy

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DESCRIPTION (provided by applicant): This proposal is in response to the Notice# NOT-OD-09-058, title: NIH announces the availability of Recovery Act Funds for Competitive Revision Applications. The broad aim of our parent grant (RO1 CA109330, "Molecular Basis of Aneuploidy") is to understand how aberrations in sister chromatid separation contribute to chromosomal missagregation and generation of aneuploidy. The purpose of the revised application is to examine the role of Separase overexpression and its mislocalization in osteosarcoma as a mechanism of aneuploidy development, and in the initiation and progression of osteogenic sarcomas. Unstable chromosome number known as aneuploidy is a hallmark of pediatric osteosarcoma. There currently is not an effective way to study this type of cancer, largely because there is no suitable animal model to investigate the mechanism of chromosomal instability in osteosarcoma. The revised application addresses a key question in osteosarcoma research and attempts to develop a new mouse model for aneuploid osteosarcoma. While tumor suppressor protein p53 and steroid hormones such as androgens have long been implicated in the development of osteosarcoma in adolescents, the precise mechanisms of their contribution are not well understood. Here we propose that Separase, an enzyme that is essential in chromosomal separation during cell division, works in conjunction with both mutations in p53 and with androgens to promote osteoblast (the cell that make growing bone) aneuploidy and osteosarcoma. To investigate this novel idea in an in vivo setting, we propose to develop and characterize genetically engineered mouse models. We plan to use murine genetic crosses to engineer molecular models that control gene expression in the mouse. The ability to combine genetic and physiological manipulations (e.g. hormone levels) will allow us to address the complex nature of osteosarcoma tumorigenesis, which is thought to be a multi-step process. The use of genomic technology will allow us to find commonalities between our mouse model(s) and human osteosarcoma. We are confident the current project will not only shed light on new mechanisms of aneuploidy contributing to osteosarcoma initiation and progression but will also provide a potential pre-clinical model that emulates several aspects of the human osteosarcoma. PUBLIC HEALTH RELEVANCE: The current project addresses a key question in osteosarcoma research that has not been addressed before and attempts to develop a new mouse model for aneuploid osteosarcoma. While tumor suppressor protein p53 and mitogenic hormones have long been implicated to play a role in osteosarcoma in adolescents, the precise mechanisms of their contributions are not well understood. Here we propose that the cohesin protease, Separase, a critical cell cycle regulating protein, works in conjunction with mutations in p53 coupled with mitogenic hormones in promoting osteoblast (the cell that make growing bone) aneuploidy and thus initiating osteosarcoma and fuelling its progression.