Abstract Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of this devastating disease has not significantly changed, and the biology of this type of cancer also remain largely unexplored. To enhance the understanding of this disease through global heath cancer research collaborative effort, we have set up an international collaboration between Forsyth Institute, Cambridge, and KaviKrishna laboratory, which is located in Kamrup district of Assam, having highest incidence of oral cancer in the world. Through this collaborative effort we intend to explore the role of hypoxia in oral cancer progression, metastasis and therapy resistance. Method: We used an oral squamous cell carcinoma cell line SSC25 for this purpose, and performed several experiments using a well-described in vitro assay of CSC self-renewal under hypoxia. Results: We identified a rare ABCG2+ expressing, highly tumorigenic cell population in SSC-25 having cancer stem cell (CSC) like characteristics in the in vivo serial transplantation assay, as well as high metastatic activity to bone marrow of NOD/SCID mice. The ABCG2+ cells, when exposed to hypoxia (<0.1% O2, 24 hours), exhibited enhanced expression and transcriptional activity of MYC, and HIF-2alpha. ChIP assay revealed that HIF-2alpha directly binds to MYC in ABCG2+ cells. siRNA inhibition of HIF-2alpha significantly reduced hypoxia-induced MYC expression and transcriptional activity in ABCG2+ cells. Finally, in clinical OSCC specimens, we confirmed the expression of MYC, HIF-2alpha and ABCG2 expression by immunohistochemistry. Conclusion: These data indicate that MYC oncogene play important role in the self-renewal of oral cancer cells during hypoxia. Citation Format: Hong Li, Joyeeta Talukdar, Sora Sandhya, Seema Bhuyan, Sukanya Gayan, Anupam Sarma, Reza Bayat Mokhtari, Dean W. Felsher, Herman Yeger, Bikul Das. MYC and HIF-2alpha cooperates in oral squamous carcinoma cell self-renewal during hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1529. doi:10.1158/1538-7445.AM2015-1529