Prior Funding

Modern oncology has begun to be alert to the heterogeneous nature of human tumors on both phenotypic and genetic level. In view the fact that diverse clones existing in tumors result in discordant drug responses and consequent tumor recurrence and metastasis, we need to identify molecular determinants of tumor heterogeneity to develop more effective cancer therapies. Cancer stem cells (CSCs) are regarded as a primary mechanism accounting for tumor heterogeneity. CSCs harbor self-renewal capacity and pluripotent differentiation property, and thus are capable of initiating growth and progression of heterogeneous tumor despite of their rareness in tumors. Discoveries on bi-directional reprograming of cancer cells (interchangeable differentiated and induced stem-like status) has revolutionized not only the prospect of targeting stem-like cancer cells for therapeutic purposes. My proposal is to delineate the mechanism underlying this dynamic process. Our preliminary data has already shown a new layer of regulatory control of CSCs, termed K63 ubiquitination. We will determine whether and how this new regulation orchestrates CSC expansion and tumor heterogeneity and develop effective CSC-targeted therapies.