Yu-Chieh (Jack) Wang, PhD

Dr. Wang received his doctoral degree in medicinal chemistry and pharmacognosy from The Ohio State University. His early research was focused on the experimental therapeutics of human cancer and the regulation of kinase signaling using novel small molecules. In addition, he has led several studies at the interface of stem cell and cancer biology with emphases on posttranslational modification-mediated regulatory mechanisms underlying cellular pluripotency and the physio-pathological development of human pigment cells. As an American Cancer Society Research Scholar, Dr. Wang works with his group to provide new insights and resolutions to help overcome challenges in biomedical research and disease treatment. Using human stem cell-based platforms and studying regenerative medicine, they strive to have a better understanding of how these novel approaches can be leveraged to model or treat disease.

Honors and Awards

• 2020 American Cancer Society (ACS) Research Scholar, American Cancer Society
• 2012 Society of Fellows Postdoctoral Travel Award, The Scripps Research Institute
• 2011 ISSCR Travel Award, International Society for Stem Cell Research (ISSCR)
• 2009 Marie Mayer Fellow, Marie & Jimmy Mayer Award for Melanoma Research
• 2007 NIH National Graduate Student Research Festival Travel Grant, National Institutes of Health
• 2004 Outstanding Student Research Award, Department of Biology, National Taiwan Normal University
• 2002 Outstanding Student Research Award, Department of Biology, National Taiwan Normal University

A research focus in the Wang lab is translational medicine aiming to understand the molecular basis of therapeutic responses in melanoma and to develop better strategies for managing patients. Besides, they have long-standing expertise and interests to study how glycoenzymes are involved in the regulation of stem cell differentiation and the developmental abnormalities in patients with congenital glycosylation/deglycosylation disorders. The active research directions in the group include:

Targeting protein glycosylation/deglycosylation as an Achilles' heel in human cancer cells
It is known that cell signaling mediated by protein glycosylation is critically involved in cell differentiation and normal development. Interestingly, many glycosylation features in cells are significantly altered during pathogenesis like cancer formation, indicating that certain glycosylation or deglycosylation mechanisms could be highly demanded by cancer cells to sustain their viability or oncogenic signaling. Therefore, the dysregulated glycosylation represents a potentially vulnerable point in cancer cells for the identification of novel therapeutic targets with the opportunity for a broad therapeutic window. We are actively investigating multiple glycoenzymes and testing their roles in the formation and progression of cancer, including melanoma and glioblastoma. We believe this study will reveal intriguing biology and address multiple challenges in cancer therapy by understanding protein glycosylation/deglycosylation as a potential Achilles' heel of cancer.

Functional significance of glycanase NGLY1 in neural differentiation and human cerebral development
As an enzyme that removes N-glycans from glycopeptides, N-glycanase 1 (NGLY1) deglycosylates denatured glycoproteins and enables proteasome-mediated protein degradation to efficiently occur. The mutations of the human NGLY1 gene that lead to NGLY1 deficiency have been recently identified as the cause of a previously undiagnosed congenital disorder. NGLY1-deficient patients often present with developmental delay accompanied by many neurological symptoms in the central nervous system. How the malfunction of NGLY1 causes these neurodevelopment-related abnormalities in the human brain remains unclear, forming a major obstacle for the development of potential therapeutic or protective approaches. Using an integrative approach based on human pluripotent stem cell (hPSC), cerebral organoid, and systems biology techniques, we are studying the cellular and molecular features during neurodevelopment in the absence of NGLY1 expression.

Using reprogramming approaches to model melanoma and dissect malignancy signaling
Advanced melanoma is highly metastatic and refractory to many therapeutic approaches. Although targeted therapies (e.g., a BRAF inhibitor) and immune checkpoint blockers (e.g., a monoclonal CTLA-4 antibody) have shown encouraging anticancer activity for treating patients with advanced melanoma, the tumor regression responses induced by these therapeutic agents are frequently unsustainable for the long term or are limited in a small subpopulation of patients. This suggests that there are resistance mechanisms in the cells hindering the anticancer effect and that identifying these mechanisms will be tremendously helpful for designing strategies to improve the therapeutic efficacy. Emerging evidence has shown that melanoma cells may develop resistance to these targeted therapies and further increase dependence on hyperactive MAPK signaling, partially due to the enhanced expression of the mutant BRAF protein. With expertise in cancer, stem cell, and systems biology, we work to elucidate the causes and effects of melanocytic cells developing their dependence on the MAPK signaling in the context of melanocyte development modeled using hPSCs.

Functional significance of protein glycosylation in pluripotency regulation
Much progress has been made toward understanding the regulation of cellular pluripotency in hPSCs at the molecular level and how to translate that knowledge into regenerative medicine. However, studies of protein expression and posttranslational modifications (PTMs) in hPSCs have lagged behind the genomic studies. Our group has previously identified several types of protein glycomodifications and glycan-binding proteins that are preferentially associated with the pluripotent state in hPSCs. We hypothesize that the glycoproteins with pluripotency-associated glycomodifications in hPSCs are functionally important for the regulation of cellular pluripotency. We are using proteomics and protein biochemistry approaches to delineate the roles of protein glycosylation in the regulation of pluripotency and potentially discover novel targets for manipulating pluripotency in cells for regenerative medicine and other biomedical applications. Currently, we are focusing on protein fucosylation and sialylation.