On-going research programs
1. Using reprogramming approaches to model melanoma and dissect malignancy signaling
Advanced melanoma is highly metastatic and notoriously refractory to many therapeutic approaches. Although vemurafenib (a BRAF inhibitor) and ipilimumab (a monoclonal CTLA-4 antibody blocking the inhibitory signal in cytotoxic T lymphocytes) have shown an encouraging anti-melanoma activity for treating patients with advanced melanoma, the tumor regression responses induced by these targeted therapy 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 of vemurafenib and ipilimumab. 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 mutant BRAF protein. With expertise in cancer, stem cell and systems biology, my group uses an interdisciplinary and innovative strategy to elucidate the causes and effects of melanocytic cells developing their dependence on oncogenic BRAF in the context of melanocyte development modeled using hiPSC techniques.
2. 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 previosuly identified several types of protein glycomodification 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 approches 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.
3. Functional significance of glycosidase 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. Defects in NGLY1 may affect the quality control and homeostasis of many cellular proteins, subsequently perturbing cell signaling pathways, normal cell physiology and organ development. 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. However, how the malfunction of NGLY1 causes these neurodevelopment-related abnormalities in the human brain is unknown, forming a major obstacle for the development of potential therapeutic or protective approaches. Using an integrative approach based on hPSC, cerebral organoid, and systems biology techniques, we are studying the cellular and molecular features during neurodevelopment in the absence of NGLY1 expression.
4. Targeting protein glycosylation/deglycosylation as an Achilles’ heel in human cancer cells
The proper regulation of protein glycosylation is relevant to the conformation, normal function and quality control of numerous proteins in 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, suggesting that certain glycosylation or deglycosylation mechanisms could be highly demanded by cancer cells to sustain their viability or oncogenic signaling. Despite the developmental abnormalities frequently found in patients with congenital glycosylation disorders where certain glycosylation mechanisms are completely lost, the existence of these patients indicates that the tolerability of manipulation of protein glycosylation in vital organs and many types of somatic cells. Therefore, the dysregulated glycosylation represent a potential vulnerable point in cancer cells for identification of therapeutic target and development of novel treatment with the opportunity for a broad therapeutic window. We are actively investigating multiple glycoenzymes and testing their roles in cancer formation and progression. 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.