Cedars Sinai Medical Center
United States of America
My major scientific interest is to investigate the molecular mechanisms underlying cancer progression to lethal disease, by developing and implementing novel and robust proteomics methods. When I was an undergraduate student, I was fascinated by the enormous structural and functional diversity of proteins, the central executors of life activities. Thus, I pursued my Ph.D. degree in a proteomics lab at Peking (Beijing) University, where I mastered various techniques in protein chemistry, mass spectrometry, and molecular and cell biology. Being intrigued by the tremendous plasticity of cancer cells and their resilience to therapeutic treatments, I pursued my postdoctoral training jointly at a prostate cancer research lab (led by Dr. Michael Freeman) and a proteomics lab (led by Dr. Hanno Steen) at Boston Children’s Hospital. At that time, the Freeman lab was investigating the molecular mechanisms underlying the prostate cancer-promoting roles of cholesterol. In mammalian cells, cholesterol promotes the formation of lipid rafts, also known as signaling hubs on the plasma membrane. Previous studies suggest that some signaling proteins are shuttled between lipid rafts and cytosol, so they can relay signals from cell surface receptors to cytosolic effector proteins. But what is the “shuttle”? It turned out to be a reversible lipid modification called palmitoylation. Nevertheless, palmitoylation was notoriously difficult to analyze. This is because palmitoylation is non-antigenic, so no antipalmitoylation antibody has ever been successively produced. Traditionally, the only available method for studying palmitoylation is using [3H]-palmitate to label cells followed by immune precipitation and days to weeks of film exposure. Thus, we developed a pamitoyl-proteomics method called PalmPISC (Palmitoyl Protein Identification and Site Characterization), and obtained many thought-provoking findings from a pamitoyl-proteomics study of prostate cancer DU145 cells. Though PalmPISC is superior to the traditional method and many other palmitoyl-proteomics methods, there is still a lot of room for improvement. As a perfectionist, I would like to develop a highly robust and user-friendly tool that can be easily adopted by other researchers. So I propose to establish a next-generation PalmPISC in this NCI Omnibus R21 grant application. In addition to method development, I am actually more interested in identifying “molecular engines” that drive, and “molecular brakes” that halt, cancer progression to metastasis and therapeutic resistance. Funded by a DoD grant, my postdoctoral fellow and I have been studying the roles of a palmitoylating enzyme DHHC2 in prostate cancer metastasis and castration resistance. In this R21 proposal, I would like to determine whether the loss of a palmitoylation brake (here a depalmitoylating enzyme called PPT1) makes prostate cancer cells more aggressive and, if yes, why. In brief, I have strong expertise in both palmitoyl-proteomics and prostate cancer research, as well as the leadership and motivation to successfully carry out the proposed study. By working closely with my mentor and co-investigators and by leveraging the outstanding resources at CedarsSinai Medical Center, I am confident that we will successfully complete the proposed study in time.
The research of Wei Yang, PhD, is focused on developing and applying leading-edge proteomics technologies to discover novel cancer biomarkers, to elucidate the molecular mechanisms underlying cancer progression to lethal diseases, and to identify novel anti-cancer therapeutic targets. In the past few years, Yang's lab has developed powerful shotgun proteomics technologies that enable deep profiling and accurate quantification of the proteome, the palmitoylproteome and the phosphoproteome. Moreover, Yang and his colleagues have applied these leading-edge technologies to elucidate the molecular basis of cancer progression in cell culture models and, more excitingly, to determine the expression, palmitoylation and phosphorylation levels of thousands of proteins in formalin-fixed, paraffin-embedded cancer specimens, a gold mine for cancer biomarker discovery.