My laboratory focuses on deciphering regulatory machinery and mechanism (e.g. E3 ubiquitin ligase and ubiquitination, metabolic enzymes and drivers, etc.) responsible for EMT and dysregulated metabolism in cancer cells and CSCs. Besides the neoplastic cancer cells, lymphocytes and macrophages are prominent residents in the tumor microenvironment. My laboratory also investigates the mechanisms underlying tumor immunity. The ultimate goal is to develop mechanism-based cancer therapeutics. We use complementary approaches including cell biological and biochemical methods, informatics tools, animal models (xenograft, syngeneic, genetically-modified, PDX and humanized mice), and clinical specimens to interrogate the following research projects:

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1)      To delineate the network of metabolic reprogramming in tumor initiation and progression. Glucose and glutamine are the most rapidly consumed nutrients by cancer cells. Recent studies have revealed a high degree of metabolic plasticity in human cancers in terms of tumor cell nutrient utilization. Aside from glucose, many cancer cells display oncogene addiction to glutamine metabolism. Glutamine not only serves as a carbon and nitrogen source in cancer cells for macromolecule biosynthesis and energy production but it also regulates signaling pathways and maintains redox homeostasis, contributing to cancer cell proliferation and survival. In contrast to the increasing knowledge about glucose and glutamine regulation in fast-cycling cancer cells, whether and how these nutrients affect CSC phenotypes and functions remains largely unknown. We are currently identifying the genetic alterations and mechanisms that underlie the glucose and/or glutamine dependency of cancer cells as well as CSCs. The knowledge would have important implications for basic science and metabolism-based targeted therapies. Results from this research program had led to several research articles including those published in Cell (2012) and Nat Commu. (2019).

 

2)      To explore regulatory machinery orchestrating EMT-driven cancer stemness and drug resistance. The CSC population preferably stays in the quiescence stage (G0 phase) and thus adversely sensitizes to chemo- or radio-therapies. Epithelial to mesenchymal transition (EMT) program is responsible for cancer progression, drug resistance, and recently is engaged in acquiring CSC properties. Thus, my research is to decode the regulatory network of EMT, which will identify new strategies to eliminate the CSC population and overcome drug resistance. Our research program has led to several highly regarded publications in Cell (2013), Molecular Cell (2016), Oncogene (2017), Cell Death & Dis (2019), etc, and was highlighted in Nat. Review Cancer, Nat. Review Drug Discovery, Cancer Discovery, Nat. Review of Urology and newspapers. 

 

3)      Development of small molecule inhibitors targeting glycolysis or EMT as new therapeutic interventions. Once novel targets for cancer prevention have been identified as described above, I will use in silico screening to develop novel therapeutic arsenals accordingly. This research program is expected to identify effective inhibitors that are anticipated to overcome drug resistance and prolong tumor remission through targeting glycolysis or EMT. 

 

4) To elucidate the role of tumor-derived metabolites in the tumor microenvironment and anti-tumor immunity. The tumor microenvironment (TME) is composed of tumor cells, stromal cells, and immune cells. Elevated glucose and glutamine uptake consumption in cancer cells is known to cause nutrient dearth in the niches that are known to suppress anti-tumor immunity. We are currently characterizing the mechanism by which tumor cell metabolism-regulating proteins impedes the responses and activities of tumor-associated macrophages and cytotoxic lymphocytes.