The research of my laboratory focuses on two directions highly relevant to cancer biology, (1) the molecular basis of programmed cell death processes (including apoptosis and ferroptosis), and their roles in human disease; and (2) the molecular basis of autophagy and its role in cancer. We also study various cancer signaling and cellular metabolic events, especially those involved in cell death/survival determination. We aim to translate our basic research finding into potential therapeutic approaches. To achieve these goals, the laboratory utilizes a combination of approaches including biochemistry, chemical biology, proteomics, molecular cell biology, high-throughput screening, 3-dimensional microfluidic cell array, and mouse modeling.
Currently, we are focusing on three topics:
Apoptosis is the major form of programmed cell death. It is executed by a subfamily of cysteine proteases known as caspases. During apoptosis, these “death executioners” are activated to attack a variety of cellular targets, and eventually lead to death of the host cells. A major caspase activation pathway in mammals is the intrinsic mitochondrial pathway. Critical for various biological events, this pathway is under close regulation in cells. Currently the lab is studying the mechanisms of such regulation. Further, using high throughput screening approach, we have identified a series of artificial small molecule modulators of this pathway, and are exploring their therapeutic potential.
Molecular mechanisms of autophagy in mammals
Autophagy, a lysosome-dependent intracellular catabolic process, has emerged as a crucial component for regulating both apoptotic and non-apoptotic cell death. As such, autophagy is involved in various human diseases ranging from immune disorders, neurodegeneration, to cancer. Currently, we are investigating the molecular mechanisms of this complicated cellular process. Our mechanistic studies mainly focus on an autophagy-specific protein kinase complex known as ULK1-ATG13-FIP200 complex. This complex directly mediates the signaling of the nutrient-sensing kinase, mTOR, thus functioning as an interface linking autophagy with metabolism, cell growth, and cancer. We are also exploring the roles of autophagy in programmed cell death and cancer treatment.
Regulation of the tumor suppressor PTEN
PTEN is a potent tumor suppressor whose gene is mutated or deleted in various human cancers with a frequency as high as that of p53. Although PTEN is a master regulator for multiple cellular functions including cell growth, migration, and programmed cell death, how PTEN itself is regulated is not well-defined. Therefore, we are studying regulation of PTEN in context of programmed cell death. Our study indicates that (1) PTEN is regulated in a highly context-specific manner, and (2) different subcellular populations of PTEN can perform distinct biological function. Currently, we are investigating the regulatory mechanisms and therapeutic implication of PTEN under two specific, cancer-relevant contexts: hypoxia and IGF signaling.