Ongoing Research Programs
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:
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.
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.
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.
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.
Jiangnan (Johnnie) Hu, MD, MS, DPhil
PhD, Neuropharmacology, University of North Texas Health Science Center; MS, Neurosurgery & Neuroscience, Wenzhou Medical University (Wenzhou, China); MD, Internal Medicine, Hainan Medical University (Haikou, China)
Victor Lin, MS
MS, Medical Science, Drexel University College of Medicine (Philadelphia, PA); BS, Biology, Washington University (St. Louis, MO)
Gabriella Mraz, BS
BS, Chemistry & Biology, Ripon College (Ripon, WI)
Amber Mull, PhD
Antos Shakhbazau, PhD
Research Specialist/Lab Manager
Rare Genetic Disorder Research Opens Door to Novel Melanoma Therapy
Genetic Engineering & Biotechnology News | November 6, 2018
Team studying rare disorder discovers novel way to target melanoma
EurekAlert! | November 5, 2018
Generation of hiPSCs
Genetic Engineering & Biotechnology News | November 14, 2014
(Lin VJT, Hu J, Zolekar A, Yan LJ, Wang YC.) Front Cell Dev Biol. 2020;8:304 PMID: 32528947 PMCID: PMC7247822 06/13/2020
(Dong, Z., Jiao, Y., Hao, Y., Wang, P., Liu, Y., Shi, J., Chitrakar, C., Black, S., Wang, Y.-C., Lee, L.J., Li, M., Fan, Y., Chang, L..) Microsystems & Nanoengineering. 02/24/2020
(Chang L, Wang YC, Ershad F, Yang R, Yu C, Fan Y.) Trends Biotechnol. 2019 11;37(11):1175-1188 PMID: 31072609 SCOPUS ID: 2-s2.0-85065091597 05/11/2019
(Zuo Z, Zolekar A, Babu K, Lin VJ, Hayatshahi HS, Rajan R, Wang YC, Liu J.) Elife. 2019 07 30;8 PMID: 31361218 PMCID: PMC6706240 SCOPUS ID: 2-s2.0-85071706842 07/31/2019
(Gdowski AS, Lampe JB, Lin VJT, Joshi R, Wang YC, Mukerjee A, Vishwanatha JK, Ranjan AP.) ACS Applied Nano Materials. 25 October 2019;2(10):6249-6257 SCOPUS ID: 2-s2.0-85074676172 10/25/2019
(Zolekar A, Lin VJT, Mishra NM, Ho YY, Hayatshahi HS, Parab A, Sampat R, Liao X, Hoffmann P, Liu J, Emmitte KA, Wang YC.) Br J Cancer. 2018 12;119(12):1538-1551 PMID: 30385822 PMCID: PMC6288164 SCOPUS ID: 2-s2.0-85055978337 11/06/2018
(Lin VJT, Zolekar A, Shi Y, Koneru B, Dimitrijevich S, Di Pasqua AJ, Wang YC.) Sci Rep. 2017 07 10;7(1):5005 PMID: 28694442 PMCID: PMC5504050 SCOPUS ID: 2-s2.0-85023172089 07/12/2017
(O'Brien CM, Chy HS, Zhou Q, Blumenfeld S, Lambshead JW, Liu X, Kie J, Capaldo BD, Chung TL, Adams TE, Phan T, Bentley JD, McKinstry WJ, Oliva K, McMurrick PJ, Wang YC, Rossello FJ, Lindeman GJ, Chen D, Jarde T, Clark AT, Abud HE, Visvader JE, Nefzger CM, Polo JM, Loring JF, Laslett AL.) Stem Cells. 2017 03;35(3):626-640 PMID: 28009074 PMCID: PMC5412944 SCOPUS ID: 2-s2.0-85016602811 12/23/2016
(Mull AN, Zolekar A, Wang YC.) Int J Mol Sci. 2015 Dec 21;16(12):30458-69 PMID: 26703580 PMCID: PMC4691150 SCOPUS ID: 2-s2.0-84951311009 12/26/2015
(Koneru B, Shi Y, Wang YC, Chavala SH, Miller ML, Holbert B, Conson M, Ni A, Di Pasqua AJ.) Molecules. 2015 Oct 30;20(11):19690-8 PMID: 26528964 PMCID: PMC6332305 SCOPUS ID: 2-s2.0-84949948608 11/04/2015
(Wang YC, Stein JW, Lynch CL, Tran HT, Lee CY, Coleman R, Hatch A, Antontsev VG, Chy HS, O'Brien CM, Murthy SK, Laslett AL, Peterson SE, Loring JF.) Sci Rep. 2015 Aug 25;5:13317 PMID: 26304831 PMCID: PMC4548446 SCOPUS ID: 2-s2.0-84940042013 08/26/2015
(Wang YC, Lin V, Loring JF, Peterson SE.) Expert Opin Biol Ther. 2015 May;15(5):679-87 PMID: 25736263 SCOPUS ID: 2-s2.0-84927617058 03/05/2015