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William E. Grizzle, PhD

William E. Grizzle, PhD, PhD
Department of Pathology
Head, Pathology Program for Translational Research in Neoplasia
Director, Tissue Collection and Banking Facility

AB-Chemistry and Physics, Harvard; Ph.D. (Biophysics) Johns Hopkins University; M.D. Johns Hopkins University; Residences in Pathology, University of Alabama at Birmingham and Vanderbilt University

Research/Clinical Interest

Biomarkers in Early Detection, Prognosis, Risk and Therapeutic Outcome; Anatomic and Clinical Pathology; Tissue Resources to Support Biomedical Research; Immunomodulation of Cancer; Aging and Cancer; Post-transcriptional Processing of Genetic Info

One area in which our laboratory works is to increase the understanding of molecular features of epithelial cancers such as prostate, pancreas, mammary, colorectal and ovarian adenocarcinomas as well as squamous cell lesions of oral cavity, esophagus, lung, cervix and skin in order to identify biomarkers associated either with early pre-invasive neoplastic lesions or with advanced stage malignant lesions, especially metastatic lesions. Of special interest are biomarkers that can be used to aid in determining prognosis or risk assessment or in predicting successful therapy. For example, the earliest putative pre-invasive lesion of the prostate is prostatic intraepithelial neoplasia (PIN); we have demonstrated the phenotypic expression of molecular markers in PIN is similar to the phenotypic expression of these same molecular markers in prostatic adenocarcinomas. We study the escape of PCa from the requirement for androgens, i.e., development of androgen resistance. We use the human xenograft tumor models CWR22, CWR22R, LNCaP, DU145 and PC-3 in nude mice to investigate androgen effects on prostate tumors and the development of androgen resistance in these tumors. These data are supplemented by in vitro studies. In colorectal adenocarcinoma (CRCs), we have identified eight molecular markers that aid in identifying aggressive subgroups of CRCs. These are p53 including the polymorphism at codon 72, Bcl-2, p27kip-1, Suppressin, MUC-1, MUC-2, MUC-4 and rabphilin. We have identified differences in prognostic usefulness of biomarkers based on the anatomic location of CRCs. Our studies also have evaluated racial differences in the expression of these molecular markers as well as racial differences in the clinical importance of the expression of these biomarkers. Our studies of colorectal, breast and prostatic neoplasia have emphasized racial differences in molecular features of carcinomas and pre-invasive neoplasia. Besides our interests in epithelial neoplasia, we have a broad interest in diffuse pulmonary diseases including pulmonary arterial hypertension as well as tissue reparative processes leading to granulation tissues and neovascularity. In general our laboratory utilizes proteomic techniques but also has capabilities in molecular biology. In addition to semi-quantitative immunohistochemistry (fluorescent or bright field), Western blotting, high throughput ELISA, multiplex immunoassays (Luminex), and we collaborate using other mass spectrometry systems in the early detection of cancers by determining the proteins of specific cancers in biological fluids such as serum. We also have automated cytomorphometric instrumentation and tissue arrays that can be used in multi-tissue analyses. Similarly, we can use gene chip and spotted array analysis in gene discovery. Thus, our studies focus on molecular epidemiology of neoplasia. Of great interest are collaborative efforts to improve the biomathematic/statistical approaches to evaluating biomarkers and multiplex methods of analysis and how bias in collecting and processing tissue samples may affect multiplex assays. Also, for the last three decades we have provided human tissues to support the research of biomedical investigators throughout North America. In this effort, sponsored primarily by the Cooperative Human Tissue Network (CHTN), we have introduced to tissue resources the utilization of quality control of tissues provided for research and we have been involved in database development for tissue resources. We also have great expertise in how fixation of tissues interacts with the stages of tissue processing to affect immunorecognition and other molecular assays. A new interest includes characterizations of the molecules involved in mitosis, especially proteins of the centriole and centrosome, post-transcriptional processing (e.g., microRNA and IRES), exosomes, and genes controlling metastasis (e.g., KISS).

Selected Publications

  1. Kojima K, Bowersock GJ, Kojima C, Klug CA, Grizzle WE, Mobley JA. Validation of a robust proteomic analysis carried out on FFPE tissues of the pancreas obtained from mouse and human. Proteomics 2012;12(22):3393-402. 3656494 
  2. Srivastava SK, Bhardwaj A, Singh S, Arora S, McClellan S, Grizzle WE, Reeed E, Singh AP. Mb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance. Carcinogenesis 2012;33(6):1149-57 3514863 
  3. Singh AP, Arora S, Bhardwaj A, Srivastava SK, Kadakia MP, Wang B, Grizzle WE, Owen LB, Singh S. CXCL12/CXCR4 signaling axis induces SHH expression in pancreatic cancer cells via ERK- and Akt- mediated activation of NF=kB: implications for bidirectional tumor-stromal interactions. J Biological Chem 2012;287(46):39115-24 3493952 
  4. Jones J, Wang H, Zhou J, Hardy S, Turner T, Austin D, He Q, Wells A, Grizzle WE, Yates C. Nuclear kaiso indicates aggressive prostate cancers and [promotes migration and invasiveness of prostate cancer cells. Am J Pathol 2012;181(6):1834-46 3483816 
  5. Qin Y, Xu J, Aysola K, Oprea G, Reddy A, Matthews R, Okoli J, Cantor A, Grizzle WE, Partridge EE, Reddy ES, Landen C, Rao VN. BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9. Am J Cancer Res 2012;2(5):540-548 3433105 
  6. Katayama H, Wang J, Treekitkarnmongkol W, Kawai H, Sasai K, Zhang H, Wang H, Adams HP, Jiang S, Chakratory SN, Suzuki F, Arlinghaus RB, Liu J, Mobley JA, Grizzle WE, Wang H, Sen S. Aurora Kinase-A inactivates DNA damage induced apoptosis and spindle assembly checkpoint response functions of p73. Cancer Cell 2012;21(2):196-211 22340593 
  7. Wang H, Jones J, Turner T, He QP, Hardy S, Grizzle WE, Welch DR, Yates C. Clinical and biological significance of KISS1 expression in prostate cancer. Am J Pathol 2012;180(3):1170-8 22226740 
  8. Bovell L, Shanmugam C, Katkoori VR, Zhang B, Vogtmann E, Grizzle WE, Manne U. miRNAs are stable in colorectal cancer archival tissue blocks. Front Biosci (Elite Ed) 2012;4:1937-40 22202009 
  9. Deng Z, Cheng Z, Xiang X, Yan J, Zhuang X, Liu C, Jiang H, Ju S, Zhang L, Grizzle W, Mobley J, Roman J, Miller D, Zhang HG. Tumor cell cross talk with tumor-associated leukocytes leads to induction of tumor exosomal fibronectin and promotes tumor progression. Am J Pathol 2012;180(1):390-398 22067905 
  10. Srivastava SK, Bhardwaj A, Singh S, Arora S, Wang B, Grizzle WE, Singh AP. MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells. Carcinogenesis 2011;12:1832-9 21983127 
  11. Singh R, Stockard CR, Grizzle WE, Lillard JAR, Singh S. Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer. Int J Oncol 2011;39(2):373-81 21637913 
  12. Fortson WS, Kayarthodi S, Fjimura Y, Xu H, Matthews R, Grizzle WE, Rao VN, Bhat GK, Reddy, ES. Histone deacetylase inhibitors, valproic acid and trichostatin-A introduce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells. Int J Oncol 2011;1:111-9. 21519790 
  13. Xiang X, Zhuang X, Ju S, Jiang H, Mu J, Zhang L, Miller D, Grizzle W, Zhang HG. miR-155 promotes macroscopic tumor formation yet inhibits tumor dissemination from mammary fat pads to the lung by preventing EMT. Oncogene 2011;30(31):3440-53. 21460854 
  14. Qin Y, Xu J, Aysola K, Begum N, Reddy V, Yulil C, Grizzle W, Partridge E, Reddy ESP, Rao V. Ubc9 mediates nuclear localiation and tumor suppression of BRCA1 and BRCA1a proteins. J Cellular Physiology 2011;226:3355-67 21344391 
  15. Zhang H-G, Grizzle WE. Exosomes and Cancer: A newly described pathway of immune suppression. Clin Can Res. 2011;17(5):959-64 21224375 
  16. Brand RE, Nolen BM, Zeh HJ, Allen PJ, Grizzle WE, Lookshin AE. Serum biomarker panels for the detection of pancreatic cancer. Clin Can Res 2011;17(4):805-16 21193998 
  17. McNally LR, Welch DR, Beck BH, Stafford LJ, Long JW, Sellers JC, Huang ZQ, Grizzle WE, Stockard CR, Nash KT, Buchsbaum DJ. KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model. Clin Exp Metastasis 2010 Dec;27(8):591-600. 20844932 
  18. Blume SW, Jackson NL, Frost AR, Grizzle WE, Shcherbakov OD, Choi H, Meng Z. Northwestern profiling of potential translation-regulatory proteins in human breast epithelial cells and malignant breast tissues: evidence for pathological activation of the IGF1R IRES. Exp. Mol. Pathol. 2010; 88(3):341-52. 20233590 
  19. Katkoori V, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, Grizzle W, Manne U, Prognostic Significance of p53 Codon 72 Polymorphism Differs with Race in Colorectal Adenocarcinoma. Clin Cancer Res. 2009;15(7):2406-16 19339276 
  20. Alder MN, Herrin BR, Sadlonova A, Stockard CR, Grizzle WE, Gartland LA, Gartland GL, Boydston JA, Turnbough CL Jr, Cooper MD. Antibody responses of variable lymphocyte receptors in the lamprey. Nat Immunol. 2008;9(3):319-27 18246071 
  21. Chakrabarti R, Jones JL, Oelschlager DK, Ta pia T, Tousson A, Grizzle WE. Phosphorylated LIM Kinases Colocalize with Gamma-Tubulin in Centrosomes During Early Stages of Mitosis. Cell Cycle. 2007;6(23):2944-52 18000399 
  22. Katkoori VR, Manne K, Vital-Reyes VS, Rodriguez C, Shanmugam C, Sthanam M, Manne U, Chatla C, Abdulkadir SA, Grizzle WE. Selective COX-2 inhibitor (celecoxib) decreases cellular growth in prostate cancer cell lines independent of p53. Biotech Histochem 2013;88(1):38-46  
  23. Grizzle WE, Bell WC, Sexton KC. Issues in collecting, processing and storing human tissues and associated information to support biomedical research. In: Translational Pathology of Early Cancer. (Eds. S Srivastava, WE Grizzle), IOS Press BV, Amsterdam, The Netherlands; 2012;531-549.  
  24. Otali D, He Q, Stockard CR, Grizzle WE. Preservation of immunorecognition by transferring cells from 10% neutral buffered formalin to 70% ethanol. Biotech Histochem (in press).  
  25. Liu L, Chu KK, Houser GH, Diephuis BJ, Li Y, Wilsterman EJ, Shastry S, Dierksen GA, Birket SE, Mazur M, Byan-Parker S, Grizzle WE, Sorscher EJ, Rowe SM, Tearney GJ. Method for quantitative study of airway functional microanatomy using Micro-Optical Coherence Tomography. PLOS ONE (in press).
  26. Gurpinar E, Grizzle WE, Shacka JJ, Mader B, Li N, Piazza NA, Russo S, Keeton AB, Piazza GA. A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy. Molecular Cancer Ther 2013 (in press).
  27. Kerr EH, Frederick PJ, Egger ME, Stockard CR, Sellers J, DellaManna D, Oelschlager D, Amm HM, Eltoum IE, Straughn JM, Buchsbaum DJ, Grizzle WE, McNally LR. Lung resistance-related protein (LRP) expression in malignant ascetic cells as a prognostic marker for advanced ovarian serous carcinoma. Annals of Surgical Oncology (in press).
  28. Grizzle WE, Srivastava S, Manne U. Translational Pathology of Cancer. In: Translational Pathology of Early Cancer. (Eds. S. Srivastava, WE Grizzle) IOS Press BV, Amsterdam, The Netherlands. 2012;7-20