Contribution of Fetal and Adult Testes Expressed to Tumor

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

? DESCRIPTION (provided by applicant): Using an unbiased genome-wide loss of function screening strategy, our group has recently identified a cohort of tumor antigens that are required for cancer cell survival. These proteins, known as cancer-testis antigens (CT-antigens), are genes whose expressions are normally biased to germ cells and trophoblastic tissues but that are also aberrantly expressed in a broad range of tumors. This restricted expression pattern affords the potential for a large therapeutic window if these CT-antigens are functionally essential for tumor cell viability. I have demonstrated that one of this cohort's members, Fetal and Adult-Testis Expressed (FATE), is selectively required for tumor but not normal cell survival. In particular, depletion of FATE in a variety of tumorigenic backgrounds leads to a loss of cell viability and the induction of apoptosis. Importantly, this defect is not observed in non-transformed cell lines from either mesenchymal or epithelial lineages. My preliminary data demonstrate that FATE localizes to the mitochondria and can attenuate the release of cytochrome c following exposure to the apoptotic stimulus staurosporine, suggesting that FATE is capable of deflecting otherwise fatal cell death signals. Additionally, I have found that FATE physically interacts with a key regulator of mitochondrial fission, Mitochondrial Fission Factor, and that the proteins have opposing effects on mitochondrial morphology indicating a potential antagonistic relationship. Taken together these data suggest FATE is a previously unidentified regulator of pro-survival processes at the mitochondria. Aim 1 of this proposal will determine the ability of FATE to confer resistance to discrete intrinsic cellular insults to identify the potentilly fatal stress signals FATE-expressing tumor cells may be capable of overcoming. Aim 2 will interrogate FATE's effect on processes that impact cell survival at the mitochondria. Aim 3 will determine FATE's functional requirement in vivo using established xenograft tumors harboring inducible shRNAs. These experiments are designed to elucidate the molecular framework that necessitates FATE's pro-survival function, the manner in which this function is carried out, and establish FATE's requirement in vivo to validate it as a therapeutic target. This research plan is supplemented with a unique training plan designed to develop the clinical and translation skills necessary for a successful career as a physician-scientist in the field of cancer cell biology.