Defining Tumorigenic Contributions of Meiotic Cancer-Testis Antigens

Cancer Testis Antigens (CTAs) are expressed in testis and/or placenta and anomalously activated in a variety of tumors. However, the mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. A cohort of CTAs are required for recombination events during meiosis, suggesting meiotic CTAs have potential to functionally contribute to the genomic stability of tumors. To assess the tumorigenic contributions of meiotic CTAs, I employed a targeted siRNA screen for five meiotic CTAs. Depletion of SYCP1 or HORMAD1 decreased tumor cell proliferation, while SYCE1 loss resulted in elevated DNA damage. Another meiotic CTA, SPO11, is a topoisomerase that induces DNA double-strand breaks during meiosis. I found that SPO11 expression not only correlates with elevated DNA damage in a variety of tumor cells, but ectopic SPO11 expression increases DNA double-strand breaks. A chemigenomics approach identified that a meiotic CTA, HORMAD1, correlates with resistance to piericidin A in non-small cell lung cancer (NSCLC). Resistance is due to a reductive intracellular environment that attenuates the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibit elevated mutation burden and reduced survival. Differential expression profiling revealed that HORMAD1 tumors are enriched for genes essential for homologous recombination (HR). Mechanistic studies find that HORMAD1 promotes RAD51-filament formation but not DNA resection during HR. Accordingly, HORMAD1 loss enhances sensitivity to gamma-irradiation and PARP inhibition. Furthermore, HORMAD1 depletion significantly reduces tumor growth in vivo. These results suggest that HORMAD1 expression specifies a novel subtype of LUAD which has adapted to mitigate DNA damage. Altogether, these finding indicate that meiotic CTAs play functional roles in altering the genomic stability of tumors and represent potential intervention strategies to enhance sensitivity to DNA damage agents and/or immunotherapies in patients.