Wei Zhang Lab

Discovery and characterization of novel oncogenes in glioma. As the first group to carry out genomic profiling in glioma, we discovered and reported in 1999 that insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in high-grade gliomas. Since then, we have made major breakthroughs in understanding how IGFBP2 contributes to cancer progression. We for the first time used a mouse model to provide evidence that IGFBP2 is an oncogene and that IGFBP2 cooperates with Akt in development of glioma (Proc Natl Acad Sci USA (104:11736-41, 2007). In a follow-up Proc Natl Acad Sci USA paper (106:16675-9, 2009), we reported that IGFBP2 upregulation results from loss of INK4a.  Continuing this work, we published another paper in Proc Natl Acad Sci USA (109:3475-80, 2012) demonstrating that IGFBP2 activates the integrin/integrin-linked kinase/NFkB pathway in vivo in our mouse model. We began to investigate the role of nuclear IGFBP2 in gliomagenesis and discovered that IGFBP2 potentiate nuclear signaling function and transcriptional program mediated by nuclear EGFR-STAT3 (Oncogene 2015 Apr 20. doi: 10.1038/onc.2015.131).  I believe that it is partially because of our work in the last 11 years that the importance of IGFBP2 in cancer is being increasingly recognized and that IGFBP2 and its pathway have emerged as a new therapeutic target. In this application, we hope to continue this success and make further important contribution to the field focusing on IGFBP2. 

My group was also one of the first few to use next-generation sequencing technology to characterize transcriptome and gene fusion. We discovered and characterized a novel gene fusion, FGFR3-TACC3, as a driver event for glioma. This paper was recently published in Journal of Clinical Investigation (123:855-865, 2013), accompanied by a commentary. This fusion gene has since been found in multiple cancer types (e.g., bladder and lung) unlike most other fusion gene reported, suggesting its fundamental role in carcinogenesis that is not restricted by tissue specificity. We are continuing on functional investigation of this fusion gene.

  • Dunlap SM, Celestino J, Wang H, Jiang R, Holland E, Fuller GN, and Zhang W.  Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad. Sci. USA 104(28):11736-41, 2007.
  • Moore L, Holmes K, Smith S, Wu Y, Tchougounova E, Uhrbom L, Sawaya R, Bruner JM, Fuller GN, Zhang W.  IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci USA 106(39):16675-9, 2009
  • Holmes KM, Annala M, Chua Y, Dunlap SM, Liu Y, Niek N, Cogdell D, Hu L, Hess K, Nykter M, Fuller GN, and Zhang W. IGFBP2-driven glioma progression is prevented by blocking a clinically significant network of integrin, ILK, and NFκB. Proc Natl Acad Sci USA 109(9):3475-80, 2012.
  • Turner K, Sun Y, Ji P, Granberg K, Bernard B, Hu L, Cogdell D, Zhou X, Yli-Harja O, Nykter M, Shmulevich I, Yung WKA, Fuller GN, Zhang W. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. Proc Natl Acad Sci USA 112(11):3421-6, 2015.
  • Parker BC, Annala M, Cogdell D, Granberg K, Sun Y, Ji P, Gumin J, Zheng H, Hu L, Li X, Yli-Harja O, Haapasalo H, Visakorpi T, Liu X, Liu CG, Sawaya R, Fuller GN, Chen K, Lang FF, Nykter M, and Zhang W. Oncogenic FGFR3-TACC3 fusion escapes miR-99a regulation in glioblastoma. J. Clinical Investigation 123(2):855-865, 2013.

Characterization of cancer genome mutational landscapes. Our group was the first group to use multidimensional scaling method to cluster glioma based on trasndcriptome. We also built the first comprehensive tissue microarray in glioma. Since the establishment of TCGA, our group has been actively involved in working groups for glioblastoma, low-grade glioma, colorectal, breast, bladder, kidney, gastric and endometrial cancers. We co-authored >10 N Eng J Med, Nature, Cell, and Nature Genetics papers reporting these studies. Our recent discovery of an aggressive form of endometrioid endometrial cancer characterized by beta-catenin mutation and Wnt pathway activation was published in Journal of National Cancer Institute (2014 Sep 10;106(9).). I am a leader of a US-China consortium investigating mutation profiles in gastric cancers in a Chinese population (PNAS 2015 Jan 27;112(4):1107-12.). Our group continues the effort in interrogating the cancer genome landscape and its impact on prognosis and therapy.

  • Liu Y, Patel L, Mills G, Lu K, Sood A, Ding L, Kucherlapati R, Mardis E, Levine D, Shmulevich I, Broaddus R, and Zhang W. Clinical Significance of CTNNB1 Mutation and Wnt Pathway Activation in Endometrioid Endometrial Carcinoma. J Natl Cancer Inst. 2014 Sep 10;106(9).
  • Chen K, Yang D, Li X, Sun B, Song F, Cao W, Brat D, Gao Z, Li H, Liang H, Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce C, Wang YM, Raghavakaimal S, Li H, Lu X, Pan Y, Chang H, Ba S, Luo L,  Cavenee W*, Zhang W*, Hao X*. Mutational Landscape of Gastric Adenocarcinoma in Chinese: Implications for Prognosis and Therapy. Proc Natl Acad Sci USA 112: 1107–1112, 2015 *Corresponding authors

Discovery of cancer prognostic factors. My group has been working on cancer marker through genomics and proteomics for 18 years. We discovered IGFBP2 as a marker for high-grade glioma as well as some other cancer types. We also discovered miR-141 as a plasma marker for colorectal cancer. As one of the seven Genome Data Analysis Centers of TCGA, we have been working on several cancer types. Focusing on the serous ovarian cancer dataset, we investigated the role of BRCA1 and BRCA2 mutations in the prognosis of this cancer and discovered that BRCA2 mutations confer the most robust effects clinically. BRCA2-mutated ovarian cancers are more responsive to front-line chemotherapy and have longer overall and progression-free survival. This clinically significant finding was published in JAMA (306:1557-65, 2011). This study has been highlighted at the TCGA website. Our recent identification of the core miRNA regulatory network for mesenchymal ovarian cancer was published in Cancer Cell (23:186–199, 2013). In this paper, we identified a novel EMT-inhibitory miRNA, miR-506. We showed, in multiple datasets covering more than 1000 patients, that miR-506 is associated with better prognosis and response to cisplatin. This study was highlighted on the cover of Cancer Cell and at the TCGA website. MiR-506 has been shown to serve as an important tool in the management of ovarian cancer, and this result has been validated by a number of recent publications. Our continued characterization of miR-506 in EMT and cellular senescence has led to two recent publications in the Journal of Pathology (one highlighted on the cover).  Our most recent investigation has shown that miR-506 targets Rad51 and sensitizes cancer cells to chemotherapy. This paper was recently published in JNCI (2015 May 20;107(7).). This is one of the major research focus in my group – linking genetic markers to therapy and therapeutic responses.

  • Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, Zhang W. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306(14):1557-65, 2011.
  • Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, Zhao Y, Reynolds S, Cheng H, Rupaimoole R, Cogdell D,Nykter M, Broaddus R, Rodriguez-Aguayo C; Lopez-Berestein G, Liu J, Shmulevich I, Sood A*, Chen K, and Zhang W. A Core microRNA Network Defines a Mesenchymal Subtype of Ovarian Cancer with Poor Survival. Cancer Cell  23, 186–199, 2013
  • Liu G, Yang D, Rupaimoole R, Pecot CV, Sun Y, Mangala LS, Li X, Ji P, Cogdell D, Hu L, Wang Y, Rodriguez-Aguayo C, Lopez-Berestein G, Shmulevich I, De Cecco L, Chen K, Mezzanzanica D, Xue F, Sood AK, Zhang W. Augmentation of Response to Chemotherapy by microRNA-506 Through Regulation of RAD51 in Serous Ovarian Cancers. J Natl Cancer Inst. 2015 May 20;107(7).

Understanding of cancer systems and gene-regulatory networks. I have long been interested in how the components of cancer systems in the forms of gene expression, gene copy number, and mutations are logically related to each other and how they regulate each other. Working with my engineering colleagues for the last 14 years, we have developed mathematical models called the Probabilistic Boolean Network to study gene-regulatory networks (Bioinformatics 18:261-274, 2002; 18:1319-1331, 2002). We have also recently developed an algorithm called MIRACLE to carry out integrated analysis of different genetic and epigenetic events such as miRNA and mRNA (Cancer Cell, 23:186–199, 2013; Cancer Research, 20:878-89, 2014). My group continues to integrate biology and informatics. My group has been funded by the National Foundation for Cancer Research for a Center for Cancer Systems Informatics to gain new insight into cancer systems.

Discovery of a novel tumor suppressor gene, MIIP. Our group discovered a novel tumor suppressor gene now officially named MIIP (formerly known as IIp45) (Proc Natl Acad Sci USA, 100:13970-75, 2003). MIIP gene is located on 1p36.22, one of the most commonly deleted regions in a wide spectrum of cancers. We discovered this gene during our search for a negative regulator of oncogenic protein IGFBP2. We reported in our PNAS paper that MIIP binds IGFBP2 and inhibits IGFBP2-mediated cellular migration and invasion. With a grant from James S. McDonnell Foundation, we found and reported that MIIP counteracts HDAC6 in microtubule regulation (Journal of Biological Chemistry, 285: 3554-3560, 2010). We showed in a collaborative study that a SNP in the MIIP gene affects risk of breast cancer (Cancer Research, 70:1024-32, 2010). We then discovered that MIIP is an important mitotic checkpoint protein and inhibits APC/Ccdc20 and block gliomagenesis (Oncogene, 29:3501-8, 2010). Our most recent studies show that the MIIP gene is frequently deleted in colorectal cancer and that MIIP mutations occur in colorectal cancer. We also have data that show MIIP is a critical regulator for EGFR turnover in lung cancer. We have recently established a MIIP conditional knockout model and found the MIIP deletion leads to spontaneous development of lymphoma. Our continued effort in this line of research will lead to important and novel insight into this 1p36 tumor suppressor gene.

  • Song SW, Fuller GN, Khan A, Kong S, Shen W, Taylor E, Ramdas L, Lang F, and Zhang W.  IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proc Natl Acad Sci USA 100:13970-75, 2003.
  • Song FF, Ji P, Zheng H, Song FJ, Wang Y, Hao X, Wei Q, Zhang W*, and Chen K*. Definition of a Functional Single Nucleotide Polymorphism in the Cell Migration Inhibitory Gene MIIP That Affects the Risk of Breast Cancer. Cancer Res. 70(3); 1024-32, 2010 *Co-corresponding author
  • Ji P, Smith SM, Wang YM, Jiang R, Song SW, Bruner J, Sawaya R, Kuan J, Yu HT, Fuller GN and Zhang W. Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP. Oncogene 29(24):3501-8, 2010.
  • Wu Y, Song SW, Sun J, Bruner JM, Fuller GN, and Zhang W. IIp45 Inhibits Cell Migration through Inhibition of HDAC6. J Biol Chem 285: 3554-3560, 2010.

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