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WANG Yuexiang
Ph.D., Principal Investigator
Laboratory of Cancer Progression and Translational Medicine
Email: yxwang76@@sibs.ac.cn
 

Research Interests or Current Research Focus
Cancer is a genetic disease caused by the accumulation of genomic alterations. Our laboratory is interested in discovering genomic events that cause human cancers. We are aiming to translate these findings into early diagnosis and treatments for these deadly diseases. Our laboratory is engaged in:

(1) Molecular mechanisms of sarcoma progression;
(2) Molecular mechanisms of non-sarcoma cancer progression;
(3) Pan-cancer genomic analysis;
(4) Development of novel diagnostic tools and novel anti-cancer drugs.

Major Research Achievement
Gastrointestinal stromal tumors (GISTs) are the most common sarcoma. Metastases account for 90% of GIST-related deaths. We demonstrate for the first time that mutational inactivation of dystrophin causes progression and metastasis in human cancers with myogenic programs, including GIST, leiomyosarcoma, and rhabdomyosarcoma. The implication is that by detecting key genetic defects such as the lack of dystrophin in myogenic cancer patients, that it may eventually be possible to predict those who will develop metastatic disease. These advances also provide a rationale for evaluating various therapies under development for muscular dystrophy as new therapeutic strategies for human myogenic cancers, highlighting that recent therapeutic successes for muscular dystrophy could also serve as anti-cancer drugs (Nature Genetics 2014, Cell Cycle 2015). The paper was highlighted by “Laboratory Investigation”, “Modern Pathology” and “BioWorld Today”, featured in “Cancer Discovery” Research Watch and selected as one of the most popular stories on nature.com.
The implementation of tyrosine kinase inhibitor (TKI) therapy has revolutionized the treatment of GIST. However, resistance presents a major clinic challenge. Effective treatment strategies for GIST patients, leading to cures, can only be attained by understanding and then targeting the full variety of drug resistance mechanisms. We show in this research involving a rigorous evaluation of the molecular resistance mechanisms that eventually lead to clinical progression. We provide insights into polyclonal heterogeneity – including KRAS mutation – as a mechanism of primary TKI resistance in GIST patients (Journal of Clinical Oncology 2015).
The developmental functions ofmyocyte-specific enhancer factor 2A (MEF2A) are unclear. We dissectthe roles of MEF2A signaling pathways in cardiovascular system and somite development employing zebrafish and in vitrocardiomyocyte model systems (Cardiovascular Research 2007, Mechanisms of Development 2006, FEBS Letters 2005, Biochemical and Biophysical Research Communications 2005). We find that Bone Morphogenetic Protein-2mediates embryonic cardiac contractility upstream ofMEF2A.These studies suggest that the BMP2-MEF2A pathway could offer new opportunities for the treatment of heart failure. We also demonstrate that Hedgehog signaling negatively regulates MEF2A to govern zebrafish somite development.

Education
1994.09-1999.07: Bachelor’s Degree in Medical Sciences, Shanghai Medical University
2001.09-2007.01: Ph.D. Degree in Biochemistry and Molecular Biology, Fudan University

Major Academic Appointments
1999-2007: Teaching and Research Assistant/Lecturer/Associate Professor, Shanghai Medical School, Fudan University
2007-2015: Postdoctoral Research Associate/Senior Research Staff Scientist/Faculty, Brigham and Women’s Hospital/Harvard Medical School
2015-present: Principal Investigator, Joint Center for Translational Medicine (Institute of Health Sciences – Shanghai Changzheng Hospital), Institute for Translational Medicine (CAS-SMMU), Shanghai, China

Honors, Certificates, and Academic Society
2016: The Excellent Overseas Returnees Award by the Ministry of Human Resources and Social Security,China
2015: 100-Talent Professorship of Chinese Academy of Sciences
2015: Best Paper Award, Musculoskeletal Research Center, Harvard University
2014: American Association for Cancer Research - GlaxoSmithKline Outstanding Scholars
2014: Harvard Chinese Life Science Annual Distinguished Research Award
2011: Research Excellence Award, Brigham and Women’s Hospital/Harvard Medical School
2011: Clinical Research Award, Brigham and Women’s Hospital/Harvard Medical School
2010: Cancer Center Research Award, Brigham and Women’s Hospital/Harvard Medical School
2008: Associate Member of American Association for Cancer Research
2006: Life Science Award, Shanghai, Meiji Dairies Corporation
2006: Outstanding Youth Award, Ministry of Health, China

Recent Publications

  1. Li K#, Cheng HB#, Li Z, Pang YZ, Jia XN, Xie FF, Hu GH, Cai QP*, Wang YX*. Genetic progression in gastrointestinal stromal tumors: mechanisms and molecular interventions. Oncotarget. (in press) 2017 (*Corresponding author)
  2. Wei ZR, Liang C, Feng D, Cheng YJ, Wang WM, Yang DJ, Wang YX*, Cai QP*. Low tristetraprolin expression promotes cell proliferation and predicts poor patients outcome in pancreatic cancer. Oncotarget. 2016;7(14):17737-17750. (* Corresponding author)
  3. Wang YX*, Fletcher JA*. Cell cycle and dystrophin dysregulation in GIST. Cell Cycle. 2015;14(17):1-2. (* Corresponding author)
  4. Wang YX, Marino-Enriquez A, Bennett RR, Zhu MJ, Shen YP, Eilers G, Lee JC, Fletcher BS, Gu ZZ, Fox EA, Antonescu CR, Fletcher CDM, Guo XQ, Raut CP, Demetri GD, van de Rijn M, Ordog T, Kunkel LM, Fletcher JA. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nature Genetics (5-year IF: 34.21). 2014;46(6):601-606.
    (highlighted by "Laboratory Investigation", "Modern Pathology" and "BioWorld Today", featured in "Cancer Discovery" Research Watch and selected as one of the most popular stories on nature.com)
  5. Serrano C#, Wang YX#, Marino-Enriquez A, Lee JC, Ravegnini G, Morgan JA, Bertagnolli MM, Beadling C, Demetri GD, Corless CL, Heinrich MC, Fletcher JA. KRAS and KIT gatekeeper mutations confer polyclonal primary imatinib resistance in GIST: Relevance of concomitant PI3K/AKT dysregulation. Journal of Clinical Oncology (5-year IF: 18.21). 2015;33(22):e93-96. (#Both authors contributed equally)
  6. Schaefer IM, Wang Y, Liang CW, Bahri N, Quattrone A, Doyle L, Mariño-Enríquez A, Lauria A, Zhu M, Debiec-Rychter M, Grunewald S, Hechtman JF, Dufresne A, Antonescu CR, Beadling C, Sicinska ET, van de Rijn M, Demetri GD, Ladanyi M, Corless CL, Heinrich MC, Raut CP, Bauer S, Fletcher JA. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nature Communications. 2017 Mar 8;8:14674. doi: 10.1038/ncomms14674.
  7. Wang Q, Liu F, Wang B, Zou F, Chen C, Liu X, Wang A, Qi S, Wang W, Qi Z, Zhao Z, Hu Z, Wang W, Wang L, Zhang S, Wang Y, Liu J, Liu Q. Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors. Journal of Medicinal Chemistry. 2016;59(8):3964-79.
  8. Maynard MA, Marino-Enriquez A, Fletcher JA, Dorfman DM, Raut CP, Yassa L, Guo C, Wang Y, Dorfman C, Feldman HA, Frates MC, Song H, Jugo RH, Taguchi T, Hershman JM, Larsen PR, Huang SA. Thyroid hormone inactivation in gastrointestinal stromal tumors. New England Journal of Medicine. 2014;370(14):1327-1334.
  9. Mariño-Enríquez A, Ou WB, Cowley G, Luo B, Jonker AH, Mayeda M, Okamoto M, Eilers G, Czaplinski JT, Sicinska E, Wang Y, Taguchi T, Demetri GD, Root DE, Fletcher JA. Genome-wide functional screening identifies CDC37 as a crucial HSP90-cofactor for KIT oncogenic expression in gastrointestinal stromal tumors. Oncogene. 2014;33(14):1872-1876.
  10. Lynn M, Wang Y, Slater J, Shah N, Conroy J, Ennis S, Morris T, Betts DR, Fletcher JA, O’Sullivan MJ. High-resolution genome-wide copy-number analyses identify localized copy-number alterations in Ewing sarcoma. Diagnostic Molecular Pathology. 2013;22(2):76-84.
  11. Ravegnini G, Mariño-Enriquez A, Slater J, Eilers G, Wang Y, Zhu M, Nucci MR,George S, Angelini S, Raut CP, Fletcher JA. MED12 mutations in leiomyosarcoma and extrauterine leiomyoma. Modern Pathology. 2013;26(5):743-749.
  12. Lee CH, Ou WB, Mariño-Enriquez A, Zhu M, Mayeda M, Wang Y, Guo X, Brunner AL, Amant F, French CA, West RB, McAlpine JN, Gilks CB, Yaffe MB, Prentice LM,McPherson A, Jones SJ, Marra MA, Shah SP, van de Rijn M, Huntsman DG, Dal Cin P, Debiec-Rychter M, Nucci MR, Fletcher JA. 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(3):929-934.
  13. Jiang Q, Liu D, Sun S, Hu J, Tan L, Wang Y, Gui Y, Yu M, Song H. Critical role of connexin43 in zebrafish late primitive and definitive hematopoiesis. Fish Physiology and Biochemistry. 2010;36(4):945-951.
  14. Chen H, Hu J, Yang J, Wang Y, Xu H, Jiang Q, Gong Y, Gu Y, Song H Generation of a fluorescent transgenic zebrafish for detection of environmental estrogens. Aquatic Toxicology. 2010 ;96(1):53-61.
  15. Zhang LF, Gui YH, Wang YX, Jiang Q, Song HY. Effect of Tbx1 knock-down on cardiac performance in zebrafish. Chinese Medical Journal. 2010;123(9):1182-1189.
  16. Gong Y, Jiang Q, Hu J, Wang Y, Song H. The effects of protocadherin18b down regulation on embryonic neurogenesis in zebrafish. Progress in Biochemistry and Biophysics. 2010, 37 (8): 897-903.
  17. MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, CorsoG, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, MeyersonML, Garraway LA. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009;4(11):e7887.
  18. Jiang Q, Liu D, Gong Y, Wang Y, Sun S, Gui Y, Song H. yap is required for the development of brain, eyes, and neural crest in zebrafish. Biochemical and Biophysical Research Communications. 2009;384(1):114-119.
  19. Sun S, Gui Y, Wang Y, Qian L, Liu X, Jiang Q, Song H. Effects of methotrexate on the developments of heart and vessel in zebrafish. Acta Biochimica et Biophysica Sinica (Shanghai). 2009 ;41(1):86-96.
  20. Xu H, Yang J, Wang Y, Jiang Q, Chen H, Song H. Exposure to 17alpha-ethynylestradiol impairs reproductive functions of both male and female zebrafish (Danio rerio). Aquatic Toxicology. 2008;88(1):1-8.
  21. Zhang YQ, Wang YX, Xu GZ, Song HY, Wang WJ. Influence of CRX gene on development of photoreceptors in zebrafish. Zhonghua Yan Ke Za Zhi. 2008;44(5):448-454.
  22. Liu D, Wang YX, Hu JY, Sun SN, Song HY. The effects of connexin43 down regulation on the development of the embryonic heart and vasculature in zebrafish. Progress in Biochemistry and Biophysics. 2008, 35(7): 766-771.
  23. Wang YX, Qian LX, Dong YX, Yao LL, Gui YH, Zhong TP, Song HY. Bone Morphogenetic Protein-2 acts upstream of Myocyte-specific Enhancer Factor 2A to control embryonic cardiac contractility. Cardiovascular Research. 2007;74(2): 290-303.
  24. Sun SN, Gui YH, Wang YX, Qian LX, Jiang Q, Liu D, Song HY. Effect of dihydrofolate reductase gene knock-down on the expression of heart and neural crest derivatives expressed transcript 2 in zebrafish cardiac development. Chinese Medical Journal. 2007;120(13):1166-1171.
  25. Sun SN, Gui YH, Song HY, Zhong T, Wang YX, Jiang Q. Folic acid antagonist methotrexate causes the development malformation of heart and down-regulates the BMP2b and HAS2 expressions in zebrafish. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9(2):159-163.
  26. Wang YX, Qian LX, Jiang Q, Dong YX, Gui YH, Zhong TP, Song HY. Myocyte-specific enhancer factor 2A is essential for zebrafish posterior somite development. Mechanisms of Development. 2006;123(10): 783-791.
  27. Zhang L, Zhong T, Wang Y, Jiang Q, Song H, Gui Y. TBX1, a DiGeorge syndrome candidate gene, is inhibited by retinoic acid. The International Journal of Developmental Biology. 2006;50(1):55-61.
  28. Liu XF, Wang YX, Jiang Q, Zhong TP, Song HY. Expression pattern of MEF2C during zebrafish embryogenesis. Fudan University Journal of Medical Sciences. 2006;33(1),89-91.
  29. Lu Y, Liu XS, Wang YX, Song HY, Zhong N. Study of microsatellite instability in epithelial ovarian tumors. Journal of Peking University (Health Sciences). 2006;38(1),62-65.
  30. Chen H, Yang J, Wang YX, Jiang Q, Xu H, Song HY. Development of a transgenic zebrafish in Which the expression of EGFP is driven by vtg1 promoter. Progress in Biochemistry and Biophysics. 2006;33(10):965-970.
  31. Wang YX, Qian LX, Yu Z, Jiang Q, Dong YX, Liu XF, Yang XY, Zhong TP, Song HY. Requirements of myocyte-specific enhancer factor 2A in zebrafish cardiac contractility. FEBS Letters. 2005;579(21):4843-4850.
  32. Wang Y, Zhong T, Qian L, Dong Y, Jiang Q, Tan L, Song H. Wortmannin induces zebrafish cardia bifida through a mechanism independent of phosphoinositide 3-kinase and myosin light chain kinase. Biochemical and Biophysical Research Communications. 2005;331(1):303-308 (Cover Photo).
  33. Qian LX, Wang YX, Jiang Q, Zhong TP, Song HY. Ethanol disrupts the formation of hypochord and dorsal aorta during the development of embryonic zebrafish. Science in China (Serial C Life Sciences). 2005, 48(6): 608-615.
  34. Wang YX, Song HY. Developmental genetics of zebrafish cardiovascular systems. Foreign Medical Sciences (Section of Genetics). 2004;27(4): 220-223.
  35. Han S, Wang YX, Song HY, Ni QX. Construction of antisense VEGF cDNA eukaryotic expression plasmid and its effect on cell proliferation and angiogenesis in pancreatic cancer cell. Chinese Journal of Hepatobiliary Surgery. 2004;10(4),220-221.
  36. Wang YX, Yang J, Ma CG, Yang XY, Song HY. VEGF121 cDNA gene transfer and expression in Vitro. Progress in Biochemistry and Biophysics. 2003;30(4):612-616.
  37. Wang YX, Guan XQ, Yang J, Mo W, Song HY. Molecular Cloning, Expression and characterization of recombinant human vascular endothelial growth factor 121. Progress in Biochemistry and Biophysics. 2002;29(3):444-448.
  38. Yang J, Wang YX, Guan XQ, Ma CG, Song HY. Preparation and functional study of an vector expressing human plasminogen Kringle 5 gene. Chinese Journal of Biotechnology. 2003;19(2),217-222.
  39. Yang J, Wang YX, Guan XQ, Ma CG, Song HY. Human plasminogen Kringle 5 cDNA clone with eukaryotic system and identification of its expression product. Fudan University Journal of Medical Sciences. 2003;30(5),409-413.
  40. Jin JJ, Wang YX, Ding Q, Li G, Qu LX, Song HY, Zhang YF. Construction of antisense VEGF121 cDNA eukaryotic expression plasmid and its effect on human bladder cancer cell. Fudan University Journal of Medical Sciences. 2003;30(4),317-320.
  41. Guan XQ, Wang YX, Mo W, Wu LC, Song HY. Purification and characterization of angiogenesis inhibitor r-K4K5. Fudan University Journal of Medical Sciences. 2001;28(1),1-4.
  42. Guan XQ, Wang YX, Wu LC, Song HY. Molecular cloning and expression of the cDNA encolding angiogenesis inhibitor K4K5 with Pichia pastoris. Chinese Journal of Biotechnology. 2001;17(2),126-130.
 
 
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