The Zheng lab at the Cancer Institute of New Jersey is interested in the control of growth and metabolism in eukaryotes, and how their aberrant regulation causes cancer and other human diseases. Through genetic and genomic approaches in model organisms, we have identified a large panel of genes involved in these processes. Our current efforts are directed at understanding their functions in normal physiology and diseases in yeast, cultured animal cells, genetically engineered mice and patient samples. Ongoing projects are supported by National Institutes of Health (R01-CA123391; R01-CA166575; R01-CA173519; R01-CA123391S1; R01-CA166575S1) that include:
Nutrient Signaling and Human Diseases
Cell growth is a process of assimilating extracellular nutrients such as amino acids and converting them into cell mass. Nutrients are not only basic cell building blocks, but also key chemical signals dictating cell growth and metabolism. Highly complex signaling modules are imbedded inside the cell to accurately transduce nutrient cues directing cellular programs such as protein synthesis and nuclear transcription. However, precisely how such signaling modules relay extracellular signals for cell growth are important but still poorly understood questions. TOR has emerged as a central regulator of cell growth and metabolism in response to nutrient signals. We are using yeast and animal cells as models to tease out key steps in nutrient sensing, growth regulation and malignant growth. Aberrant nutrient signaling is a key contributor to diverse human diseases. For example, poor control of nutrient homeostasis is a major cause for cancer, diabetes, obesity and cardiovascular diseases. We are further investigating how aberrant nutrient signaling results in hyper-activation of TOR pathway and promote pathological changes such as oncogenic transformation.
Metabolic Stress and Cancer
During cell energy metabolism, by-products known as reactive oxygen species (ROS) are produced. ROS oxidizes macromolecules such as DNA and protein and causes metabolic stress. At a low level, ROS causes DNA mutations, which is a major factor in carcinogenesis. At a high level, ROS results in cell death and damages to tissues and organs. Because of the adverse effects, the cell has developed the ability to sense ROS level, and to closely coordinate metabolic activity and cellular defense mechanisms against ROS. For example, we found that the tumor suppressor ATM kinase senses ROS and activates a novel function of Sod1 as a transcription factor to promote the expression of antioxidant genes. We are investigating the mechanisms by which the cell coordinates cell metabolism and oxidative stress response under different environmental and pathological conditions. Due to elevated metabolic activity, cancer cells produce very high levels of ROS. Thus they are highly dependent on anti-oxidative mechanisms for survival. We are currently developing new anticancer strategies to explore this vulnerability of human malignancies.
TOR forms two distinct protein complexes TORC1 and TORC2, regulating cell growth and survival, respectively. TOR pathway is frequently hyper-activated in human cancers, rendering oncogenic advantages in growth and survival. Several TORC1-specific inhibitors are already approved by FDA for use in the clinic as anticancer drugs, which include the natural product drug rapamycin (sirolimus) and rapamycin analogs (everolimus and temsirolimus). More recently, TOR kinase inhibitors, which have the advantage of targeting both TORC1 and TORC2, are being tested in human clinical trials. We are interested in understanding how cancer patients respond differently to these TOR inhibitors. Through a better understanding of the genetic and molecular basis of drug sensitivity and resistance, we hope to develop personalized treatment of cancer patients with TOR-targeted therapeutics.