The Wan laboratory, established on November 1, 2015, is affiliated with the Department of Molecular Oncology of the Division of Basic Sciences at the H. Lee Moffitt Cancer Center and Research Institute located in Tampa, Florida.
The major focus of the lab is on the mechanisms of how protein post-translational modifications shape the proteomic networks and how cancer cells rewiring central signaling pathways to gain proliferative advantage as well as to acquire drug resistance. Our long-term goal is to understand the complexity and heterogeneity of protein post-translational modifications, which will eventually lead to the identification of novel personalized cancer therapeutic strategies. We are currently dedicated to various projects revealing the central roles of the Anaphase Promoting Complex and the ubiquitin signaling pathway in cancer development and evolution.
To achieve these goals, we utilize a combination of human cancer cell lines, preclinical animal models, and high-throughput screening approaches along with state-of-the-art biophysical approaches as well as bioinformatics through collaboration with experts in the field.
UNDERSTAND and CURE, for CANCER.
Genetic datasets revealed that as a whole, the deletion or mutation of the APCCdh1 ubiquitin E3 ligase complex is found in 14-20% of melanoma patients (cbioprotal.org). As one of the two co-activators for the APC, Cdh1 associates with the APC core complex to govern M-G1 cell cycle transition. There is mounting evidence indicating a tumor suppressive role for Cdh1. However, molecular mechanisms underlying Cdh1 genetic alterations or post-translational inactivation induced tumorigenesis remain largely unclear. Our recent reports have pinpointed a crucial role of APCCdh1 in controlling melanocytes pigmentation and melanoma development, suggesting its potent tumor suppressive role in melanoma development. One of our projects aims to functionally characterize the crucial role of Cdh1 and APC components in melanoma progression and phenotypic alteration. To achieve this, we have developed an experimental platform combination of protein proteomics, cellular tumorigenesis, in vitro melanocyte transformation as well as in vivo genetic mouse modeling approaches, aiming to systematically understand the functions of APCCdh1 in melanomagenesis.
Overexpression or hyperactivation of Cdc20 has been observed in a variety of human cancers. For example, in adult T-cell leukemia (ATL) patients, the viral oncoprotein Tax promotes cellular transformation in part through activating APCCdc20, a critical M phase driver, to enhance proliferation, and as proposed in this study, to evade apoptosis. The goal of this project is to uncover a novel oncogenic role of the APCCdc20 ubiquitin E3 ligase complex in allowing cancer cells to evade chemotherapeutic agents-induced cellular apoptosis, thereby promoting oncogenesis and conferring multidrug resistance. Our recent report showed that the protein levels of the pro-apoptotic protein, Bim, were low in M phase when Cdc20 is most active. Moreover, Bim protein abundance but not mRNA level was significantly elevated in multiple cell lines after depletion of endogenous Cdc20. Further studies revealed that Cdc20 directly binds to Bim and promotes its ubiquitination and subsequent degradation by the 26S proteasome. Strikingly, Bim expression is remarkably low in Human T-cell Lymphotropic Virus type I (HTLV-I)-infected T cell lines with elevated Cdc20 activity, and consistently, these cells are resistant to various anti-mitotic and DNA damage agents. In this project, we plan to determine the physiological role of APCCdc20 activation in suppressing apoptosis, as well as to explore whether targeted inhibition of Cdc20 or introducing BH3-mimetic suppresses the development of ATL or other Cdc20-overexpressing cancer including head and neck cancer in vivo.