Dr. Bing-Cheng Wang received his Ph.D. in Toxicology and Oncology from University of Wisconsin-Madison in 1991. After a postdoctoral fellowship with Dr. Erkki Ruoslahti at the Sanford Burnham Prebys Institute (formerly La Jolla Cancer Research Foundation), California, he joined the faculty of the Department of Medicine, MetroHealth Medical Center, and Case Western Reserve University School of Medicine in 1997. He is currently John A. and Josephine B. Wootton Professor in Research.
I focus on the molecular mechanisms governing cell migration and proliferation, and experimental therapy of cancer metastasis using tumor-targeting peptides.
Research Information
Research Projects
The highly successful research program in the Wang laboratory focuses on the structure, signaling, functions and therapeutic targeting of Eph family receptor tyrosine kinases (RTK) in cancer. The 14 members of Eph kinases are by far the largest subfamily of RTKs in mammal. They interact with the membrane-anchored ligands called ephrins and mediate cell-cell contact signaling.
Over the past two decades, the Wang lab made multiple seminal contributions to our current understanding of Eph kinases in tumor etiology and malignant progression. We were the first to elucidate the tumor suppressor function of EphA2 through ligand-dependent canonical signaling characterized by tyrosine phosphorylation, leading to suppression of Ras/ERK and PI3/Akt pathways (Nature Cell Biology 2020 and 2021). On the flip side of the coin, we were also the first to characterize the noncanonical, oncogenic function of EphA2 associated with serine 897 phosphorylation (pS897) that drives malignant progression and drug resistance (Cancer Cell 2009, Oncogene 2015). Based on these discoveries, we have developed drug-like small molecules targeting EphA2 (Eur. J. Med. Chem, 2017, J. Med. Chem, 2020). More recently, using a novel Time-Resolved Live Cell Spectroscopy technology called PIE-FCCS, we unexpectedly discovered that EphA2 is assembled into homotypic multimers in live cells, the first such assembly for an RTK. More importantly, the unusual assembly underlies the diametrically opposing functions of EphA2 in tumor development and progression (Science, 2023), and uncovers new avenues to develop agents targeting Eph receptors in cancer.
Current Projects
- Quantitating membrane protein interactions in live cells using time-resolved live cells spectroscopy: To characterize the molecular basis of heterotypic and homotypic assembly of protein complexes in the live cells and determine their roles in tumorigenesis.
- EphA2 non-canonical signaling: Determine how EphA2 non-canonical signaling through pS897 regulates tumor malignant progression and drug resistance.
- Immune evasion: Investigate the mechanisms of EphA2-mediated tumor immune evasion.
- Mechanism-based cancer therapeutics: Develop novel Eph kinase-targeted agents, including small molecule agonists, PROTAC degraders, and single chain antibodies to treat cancer alone or in combination with other targeted drugs or immune check point inhibitors.
Publications
Shi X, Lingerak R, Herting CJ, Ge Y, Kim S, Toth P, Wang W, Brown BP, Meiler J, Sossey-Alaoui K, Buck M, Himanen J, Hambardzumyan D, Nikolov DB, Smith AW, Wang B. Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly. Science. 2023, 382:1042-1050. doi: 10.1126/science.adg5314. PubMed PMID: 37972196
Jeon HM, Kim JY, Cho HJ, Lee WJ, Nguyen D, Kim SS, Oh YT, Kim HJ, Jung CW, Pinero G, Joshi T, Hambardzumyan D, Sakaguchi T, Hubert CG, McIntyre TM, Fine HA, Gladson CL, Purow BW, Park JB, Park MJ, Nam DH, Lee J. Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling. Cancer Cell. 2023 41:1480-1497.e9. doi: 10.1016/j.ccell.2023.06.007PubMed PMID: 37451272; PubMed Central PMCID: PMC10530238.
Volz C, Breid S, Selenz C, Zaplatina A, Golfmann K, Meder L, Dietlein F, Borchmann S, Chatterjee S, Siobal M, Schöttle J, Florin A, Koker M, Nill M, Ozretić L, Uhlenbrock N, Smith S, Büttner R, Miao H, Reinhardt HC, Rauh D, Hallek M, Acker-Palmer A, Heukamp LC, Wang B, Ullrich RT. Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Rep. 2020 31:107568. doi: 10.1016/j.celrep.2020.107568. PubMed PMID: 32348765.
Petty A, Idippily N, Bobba V, Geldenhuys WJ, Zhong B, Su B, Wang B. Design and synthesis of small molecule agonists of EphA2 receptor. Eur J Med Chem. 2018 143:1261-1276. doi: 10.1016/j.ejmech.2017.10.026. PubMed PMID: 29128116
Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 16:9-20. doi: 10.1016/j.ccr.2009.04.009. PubMed PMID: 19573808
Jun G, Guo H, Klein BE, Klein R, Wang JJ, Mitchell P, Miao H, Lee KE, Joshi T, Buck M, Chugha P, Bardenstein D, Klein AP, Bailey-Wilson JE, Gong X, Spector TD, Andrew T, Hammond CJ, Elston RC, Iyengar SK, Wang B. EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genet. 2009:e1000584. doi: 10.1371/journal.pgen.1000584. PubMed PMID: 19649315
Guo H, Miao H, Gerber L, Singh J, Denning MF, Gilliam AC, Wang B. Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res. 2006 66:7050-8. doi: 10.1158/0008-5472.CAN-06-0004. PubMed PMID: 16849550.
Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, Rhim JS, Sedor JR, Burnett E, Wang B. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001 3:527-30. doi: 10.1038/35074604. PubMed PMID: 11331884.
Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 2:62-9. doi: 10.1038/35000008. PubMed PMID: 10655584.