Modeling Apoptotic Suppression in a Mouse Model of Brain Tumors

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DESCRIPTION (provided by applicant): Glioma, the most common primary brain tumor, remains incurable. Developing effective treatments depends on a better understanding of relevant cellular programs responsible for generating these tumors. An emerging concept in cancer research contends that activation of proliferative cellular processes is insufficient to cause tumor progression without concomitant suppression of apoptosis. The primary objective of this research proposal is to investigate the contribution of anti-apoptotic genes on the initiation, maintenance, and progression of glioma. Genes in the Signal Transducer and Activator of Transcription (STAT) signaling pathway are overexpressed in glioma and this pathway is a central hub of multiple cellular programs relevant to gliomagenesis including apoptotic suppression. The STAT3 gene, in particular, is associated with the aggressive mesenchymal subtype of glioma. Our hypothesis is that apoptotic suppression mediated by the STAT signaling pathway plays a causal role in the inexorable malignant progression of glioma. We will test this hypothesis by expressing genes in the STAT signaling axis in vivo to elucidate the effects of STAT pathway activation on glioma progression. Currently, most research evaluating gene overexpression in vivo is performed with xenograft models in immunodeficient mice that fail to recapitulate the microenvironment of brain tumors. These models use tumors formed by the implantation of fully malignant cells, rather than arising from a transformational event in a normal cell, thus obscuring analysis of the impact of a gene on the critical stages a tumor must overcome during its evolution. To study how anti-apoptotic genes affect tumor development we will employ a method of somatic cell transfer using the RCAS/tv-a system. This model permits the study of gene expression on endogenous tumor formation from its putative cell of origin in an immunocompetent mouse. Importantly, this model can be used to study the effect of immunosuppression on glioma progression as tumor-induced immunosuppression is mediated by STAT signaling. Our preliminary studies indicate that the anti-apoptotic genes in the STAT signaling pathway (including Bcl-2 and STAT3) enhance tumor formation, decrease survival, facilitate immunosuppressive intra-tumoral macrophages, and increase malignant progression by inducing necrosis - the hallmark of high-grade glioma. To investigate the impact of anti-apoptotic signaling programs and characterize their function, genes in the STAT signaling axis will be expressed using the RCAS/tv-a system. Specifically, we will investigate the roles of the Bcl2 (Specific Aim 1) and STAT gene families (Specific Aim 2) on tumor formation and progression. We expect to discover their contribution to the malignant degeneration of glioma and their promotion of tumor- induced immunosuppression. Ultimately, our results will help define therapeutic targets for glioma and the model will be used to test novel therapeutics against this deadly disease.