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.
Many cancer therapies are limited in their effectiveness due to toxic side-effects on healthy tissues. I propose to study a protein, Fetal and Adult-Testes Expressed (FATE), which is necessary for survival of tumor, but not normal cells, and, is found expressed in few normal tissues. These two features make FATE an attractive therapeutic target and elaborating its function will allow for the design of tumor-specific therapies with significantly lower off-target side effects.
| Maxfield, Kimberly E; Taus, Patrick J; Corcoran, Kathleen et al. (2015) Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nat Commun 6:8840 |
