Investigating the Functional Contributions and Tumorigenic Potential of Cancer/Testis Antigens and Their Interacting Partners

Cancer/Testis (CT) antigens are proteins whose presence is normally restricted to gametogenic cells but are aberrantly activated in cancer. Due to the normal expression in immune-privileged sites, CT antigens can induce an immune response when expressed elsewhere. As a result, several studies have investigated CT antigens' expression patterns in cancer and their use as immunotherapy targets but not their functional contributions. Here I describe my work on the CT antigen FATE1 in Ewing sarcoma and the CT antigen gain-of-function screen using immortalized human colonic epithelial cells (HCEC). Ewing sarcoma is characterized by a pathognomonic chromosomal translocation that generates the EWSR1-FLI1 chimeric transcription factor. The transcriptional targets of EWSR1-FLI1 that are essential for tumorigenicity are incompletely defined. Here, I found that EWSR1-FLI1 modulates the expression of FATE1 and associates with the GGAA repeats within FATE's proximal promoter. Importantly, I found that FATE1 is required for survival and anchorage-independent growth in Ewing sarcoma cells. Our data suggests FATE1 attenuates the accumulation of BNIP3L and IB, actions that appear to be mediated by the E3-ligase RNF183. Additionally, I found FATE1 regulates autophagy and mitochondrial fission/fusion dynamics. Overall, I propose that engaging FATE1 function can permit the bypass of cell death mechanisms that would otherwise inhibit tumor progression. Previously, our group has demonstrated that several CT antigens performed functional roles in various cancers. Through utilizing the HCEC cell lines, I found that a subset of tested CT antigens increased soft agar colony formation, including the kinase TSSK6. Interestingly, I found that TSSK6 activates WNT signaling, a pathway known to be aberrantly activated in colorectal cancer and is important for cancer cell viability. Further investigation revealed that several of TSSK family members and TSSK6 activating chaperone, TSACC, are enriched in cancer and are important for tumor cell viability. Overall, these studies demonstrate that CT antigens can be actively expressed in cancer by oncogenic transcription factors and have functional roles that promote tumorigenesis.