Mammalian cell is a highly dynamic and complex machinery, where activities of large number of molecular components are interconnected and intricately coordinated by controls and regulations at the system level as modules of pathways and networks. The main research interest of my lab is to unravel such complexity of pathway/network dynamics in cancer and anticancer drug response by using quantitative microscopy and empirical modeling.
Cancer is by nature a systematic disease: it is the result of accumulation of hundreds of genetic mutations; and these mutations are highly variable between different cancer types and tumor samples. To understand such distinct variability and the underlying molecular changes that give rise to carcinogenesis, one has to be very quantitative, as diverse cancers and normal tissues are likely to differ from each other in the levels of proteins, and activities of pathways, rather than in the complete presence/absence of particular pathways. In another word, the key to understand cancer and differential drug response in cancer is to quantify how variation in reaction rates and protein concentrations, a result of both mutation and environmental stress, can lead to distinct global phenotype, and also how much such local change in the system is necessary and sufficient for cancer induction and development of anticancer drug resistance. In my lab, we combine quantitative microscopy, including high-throughput automatic microscopy and time-lapse live cell microscopy, with computational modeling, to identify cellular alterations in response to anticancer drugs and quantify kinetics of drug induced changes in specific cellular pathways, in particular the apoptotic pathway that triggers cell death. These results provide new insight into not only anticancer drug mechanism but also cell-type variation in drug response. The ultimate goal is to acquire a quantitative and mechanistic understanding of the concerted dynamic changes induced by anticancer drugs in different cell types, and eventually to predict drug response in different cancer.
Below are three main research topics in the lab.
- Profile compounds and cell lines based on single-cell imaging using high-throughput automatic microscopy; compare phenotypic responses between different human cancer cell types and normal cells; compare cellular response to different anticancer reagents.
- Develop real-time microscopy assays to measure kinetics of drug-induced molecular alterations in vivo. Determine kinetic variations that are cell-type specific and/or drug specific. Identify molecular targets that are critical for drug-induced alterations, especially in the apoptotic pathway
- Develop quantitative cellular pathway/network models for the observed pharmacokinetic/pharmacodynamics; identify variables and constraints essential for pathway activities from the empirical models