Abstract IA18: Mechanistic participation of cancer testes antigens in tumor initiation and progression

Abstract

Abstract Tumors frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which the anomalous expression of CTAs represents epiphenomenon or confers tumorigenic traits is unknown. To gain a systems level view of CTA activity, we implemented a multidimensional functional genomics approach that incorporated seven different phenotypic assays in 11 distinct disease settings. This analysis identified 16 CTAs that are essential for tumor cell viability and 10 CTAs that are pathological drivers of HIF, WNT or TGFb signaling. In particular, we discovered that Fetal and Adult Testis Expressed 1 (FATE1), is a key survival factor in multiple oncogenic backgrounds. FATE1's mechanism of action is to prevent the accumulation of the stress sensing, BH3-only protein, BIK, thereby permitting viability in the presence of toxic stimuli. Importantly, FATE1 expression correlates with significantly decreased survival time in colorectal and lung cancer patients. We also found that the CTA, ZNF165, promotes TGFb signaling by directly inhibiting the expression of negative feedback regulatory pathways. This action is essential for survival of triple negative breast cancer (TNBC) cells in vitro and in vivo. Given these robust phenotypes, we hypothesize that ectopically expressed testes proteins can buttress deviant tumor cell processes that promote tumor initiation and progression. Citation Format: Angelique Whitehurst. Mechanistic participation of cancer testes antigens in tumor initiation and progression [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA18.