Yuan Gao, PhD

The primary research objective in the Gao lab is to uncover novel fundamental mechanisms underlying gene expression in cancers. The gene expression programs that specify and maintain cell function are regulated by transcription factors (TFs) and their accessory proteins. Alterations in transcription factor (TF) activity are pervasive across numerous cancer types and result in aberrant gene expression programs that dysregulate cell differentiation and proliferation. However, direct chemical targeting of TFs remains challenging, which poses an urgent need for the identification of TF-modulation strategies for therapeutic intervention. 

During my postdoctoral training with Dr. Vakoc at the Cold Spring Harbor Laboratory, I discovered that the ETS family transcriptional repressor ETV6 is a unique dependency in Ewing sarcoma, which is a highly aggressive bone cancer that affects children and young adults. I identified a detailed mechanism underlying how targeting of ETV6 converts EWS-FLI1 from an oncoprotein into a tumor suppressor by reprogramming its genomic occupancy. Notably, ETV6 is largely dispensable for homeostasis in the majority of mammalian tissues, making this TF an attractive target for this pediatric tumor. However, transcription factors, like ETV6, are considered 'undruggable' targets due to a lack of suitable small-molecule pockets. To challenge this notion, I profiled metabolites that can bind ETV6 to uncover its endogenous chemical ligands. These efforts were inspired by the nuclear hormone receptor protein family, where knowledge of metabolite binding sites has allowed for effective pharmacological strategies. Using a biochemical screening strategy, I discovered a specific interaction between phosphatidic acid and ETV6. Further characterizations indicate that this ligand binds to the SAM domain of ETV6 and regulates its oligomerization. Since ETV6 oligomerization is critical to support Ewing sarcoma, I intend to deepen the biochemical and genetic evaluation of this ETV6 ligand with the long-term goal of leveraging these insights to develop tool compounds and drugs that modulate this TF. Going forward, my laboratory will combine innovative genetic screening methodologies with biochemical and structural tools to advance targeted therapies in Ewing sarcoma, and ultimately other cancers. A key hypothesis underlying my research is that transcriptional and epigenetic machineries are allosterically regulated by yet-to-be discovered endogenous metabolites. Elucidation of such mechanisms will reveal fundamental regulatory mechanisms and can potentially provide opportunities to develop novel pharmacology.