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David J. DeGraff

TitleAssistant Professor
InstitutionCollege of Medicine
DepartmentPathology
Address500 University Drive Hershey, PA 17033
Mailbox: HO83
Phone717-531-0003 Ext 281295
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    Collapse Biography 
    Collapse awards and honors
    2013NIH Pathway to Independence Award (K99/R00), National Cancer Institute
    2013New Investigator Award, Bladder Cancer Advocacy Network
    2010Postdoctoral Fellowship, Department of Defense
    2011Travel award, Society for Basic Urologic Research
    2009Postdoctoral Fellowship, American Cancer Society
    2009Travel award, NIDDK Genetics of Urologic Malformations meeting
    2009Travel award, Society for Basic Urologic Research
    2009John Quale Travel award, Bladder Cancer Advocacy Network
    2009Trainee, Integrated Biological Systems Training in Oncology , Vanderbilt University Medical Center
    2008Trainee, Multidisciplinary training in Molecular Endocrinology , Vanderbilt University Medical Center
    2007Trainee, Integrative Graduate Education and Research (IGERT), University of Delaware
    2006Travel award, Society for Basic Urologic Research
    2004University Graduate Fellowship, University of Delaware
    2002Reisher Scholarship Recipient, Metropolitan State University of Denver

    Collapse Overview 
    Collapse overview
    Title:
    Assistant Professor of Pathology, Surgery, and Biochemistry & Molecular Biology
    Member, Penn State Hershey Cancer Institute

    Education:
    Post-Doctoral training, Department of Urologic Surgery, Vanderbilt University Medical Center
    Ph.D., University of Delaware
    B.S., Metropolitan State University of Denver

    Narrative:
    In 2014, it is estimated that approximately 74,690 people will be diagnosed with bladder cancer in the United States. For reasons that we still do not understand completely, men are much more likely to be diagnosed with bladder cancer than women. Over fifteen thousand people will die from this disease in 2014. Bladder cancer tumors that progress to a stage defined by muscle invasion (MI) are especially dangerous, and require extensive surgery. Unfortunately, surgery is not always curative for MI bladder cancer. Yet, treatment advances for bladder cancer patients have been lacking. Therefore, there is a desperate need for novel therapeutic approaches for the treatment of bladder cancer.

    One area potentially ripe for the development of novel therapeutic approaches involves the identification of molecular pathways that control tumor differentiation and histological subtype. While ninety percent of bladder cancer is histopathologically classified as urothelial cell carcinoma (UCC), approximately 20-40% of MI UCC exhibits mixed histology with squamous components, and patients with this type of bladder cancer exhibit relatively poor clinical outcomes. As translational biologists, we hypothesize that new discoveries for the treatment of bladder cancer patients will derive, at least in part from our increased understanding of the molecular mechanisms that are related to mixed urothelial/squamous differentiation. Specifically, we focus on the role of transcription factors in this process, which are master regulators of urothelial differentiation and gene expression.

    One such family of transcription factors is the forkhead box (FOX) family of transcription factors. This family contains 43 members in mammals implicated in a variety of malignancies. The ability of FOXA1 to act in the modulation of chromatin structure by “pioneering” increased accessibility for transcription factors to access downstream target genes appears to be central to its influence on tumor biology.

    We recently reported that loss of FOXA1 expression is significantly associated with advancing human BLCa tumor stage and grade, and that FOXA1 loss occurs in KSM and in 81% of SCC, as well as 40% of UCC. We have also shown that FOXA1 loss is associated with poor survival in bladder cancer patients, and that genetic ablation of FOXA1 causes sex-specific changes in the bladder urothelium, similar to the case in humans. In addition to follow up studies based on these observations, we are now in the process of identifying key regulatory networks which interact with FOXA family members to regulate urothelial biology, and which additionally mediate chemosensitivity.

    We use a variety of techniques (various in vitro approaches, several in vivo approaches including transgenic and knockout mouse models, and tissue recombination xenografting) in the laboratory to identify pathways important for disease progression, which may also serve as new targets. In addition, we work closely with our clinical colleagues (urologic surgeons and genitourinary pathologists) to identify targets and work on ways to bring new approaches to the clinic.


    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Flaig TW, Kamat AM, Hansel D, Ingersoll MA, Barton Grossman H, Mendelsohn C, DeGraff D, Liao JC, Taylor JA. Proceedings of the 3rd Annual Albert Institute for Bladder Cancer Research Symposium. Bladder Cancer. 2017 Jul 27; 3(3):211-223. PMID: 28824949.
      View in: PubMed
    2. Warrick JI, Kaag M, Raman JD, Chan W, Tran T, Kunchala S, Shuman L, DeGraff D, Chen G. FOXA1 and CK14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their associated conventional urothelial carcinoma. Virchows Arch. 2017 Jul 18. PMID: 28721490.
      View in: PubMed
    3. Warrick JI, Walter V, Yamashita H, Chung E, Shuman L, Amponsa VO, Zheng Z, Chan W, Whitcomb TL, Yue F, Iyyanki T, Kawasawa YI, Kaag M, Guo W, Raman JD, Park JS, DeGraff DJ. FOXA1, GATA3 and PPAR? Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines. Sci Rep. 2016 Dec 07; 6:38531. PMID: 27924948.
      View in: PubMed
    4. Yamashita H, Amponsa VO, Warrick JI, Zheng Z, Clark PE, Raman JD, Wu XR, Mendelsohn C, DeGraff DJ. On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer. Nat Rev Urol. 2017 Feb; 14(2):98-106. PMID: 27898096.
      View in: PubMed
    5. Shah TS, Kaag M, Raman JD, Chan W, Tran T, Kunchala S, Shuman L, DeGraff DJ, Chen G, Warrick JI. Clinical significance of prominent retraction clefts in invasive urothelial carcinoma. Hum Pathol. 2017 03; 61:90-96. PMID: 27818288.
      View in: PubMed
    6. Raman JD, Warrick JI, Caruso C, Yang Z, Shuman L, Bruggeman RD, Shariat S, Karam JA, Wood C, Weizer AZ, Remzi M, Haitel A, Bensalah K, Rioux-Leclerq N, Bolenz C, Roscigno M, Krabbe LM, Kapur P, Lotan Y, Margulis V, DeGraff DJ. Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract. Urology. 2016 Aug; 94:314.e1-7. PMID: 27215483.
      View in: PubMed
    7. Warrick JI, Raman JD, Kaag M, Bruggeman T, Cates J, Clark P, DeGraff DJ. Enhancer of zeste homolog 2 (EZH2) expression in bladder cancer. Urol Oncol. 2016 Jun; 34(6):258.e1-6. PMID: 26976725.
      View in: PubMed
    8. Warrick JI, Kaag M, Raman JD, Chan W, Tran T, Kunchala S, DeGraff D, Chen G. Squamous Dysplasia of the Urinary Bladder: A Consecutive Cystectomy Series. Int J Surg Pathol. 2016 Jun; 24(4):306-14. PMID: 26860905.
      View in: PubMed
    9. Grabowska MM, Kelly SM, Reese AL, Cates JM, Case TC, Zhang J, DeGraff DJ, Strand DW, Miller NL, Clark PE, Hayward SW, Gronostajski RM, Anderson PD, Matusik RJ. Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia. Endocrinology. 2016 Mar; 157(3):1094-109. PMID: 26677878; PMCID: PMC4769366 [Available on 03/01/17].
    10. Wu XR, Mendelsohn C, DeGraff DJ. Tumorigenicity of RTK/RAS in urothelium. Oncoscience. 2015; 2(9):739-40. PMID: 26501074; PMCID: PMC4606002.
    11. Adam RM, DeGraff DJ. Molecular mechanisms of squamous differentiation in urothelial cell carcinoma: a paradigm for molecular subtyping of urothelial cell carcinoma of the bladder. Urol Oncol. 2015 Oct; 33(10):444-50. PMID: 26254697.
      View in: PubMed
    12. Reddy OL, Cates JM, Gellert LL, Crist HS, Yang Z, Yamashita H, Taylor JA, Smith JA, Chang SS, Cookson MS, You C, Barocas DA, Grabowska MM, Ye F, Wu XR, Yi Y, Matusik RJ, Kaestner KH, Clark PE, DeGraff DJ. Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer. Am J Pathol. 2015 May; 185(5):1385-95. PMID: 25907831; PMCID: PMC4419202.
    13. Grabowska MM, DeGraff DJ, Yu X, Jin RJ, Chen Z, Borowsky AD, Matusik RJ. Mouse models of prostate cancer: picking the best model for the question. Cancer Metastasis Rev. 2014 Sep; 33(2-3):377-97. PMID: 24452759; PMCID: PMC4108581.
    14. Lin-Tsai O, Taylor JA, Clark PE, Adam RM, Wu XR, DeGraff DJ. Progress made in the use of animal models for the study of high-risk, nonmuscle invasive bladder cancer. Curr Opin Urol. 2014 Sep; 24(5):512-6. PMID: 24921908.
      View in: PubMed
    15. Yu X, Cates JM, Morrissey C, You C, Grabowska MM, Zhang J, DeGraff DJ, Strand DW, Franco OE, Lin-Tsai O, Hayward SW, Matusik RJ. SOX2 expression in the developing, adult, as well as, diseased prostate. Prostate Cancer Prostatic Dis. 2014 Dec; 17(4):301-9. PMID: 25091041; PMCID: PMC4227931.
    16. DeGraff DJ, Grabowska MM, Case TC, Yu X, Herrick MK, Hayward WJ, Strand DW, Cates JM, Hayward SW, Gao N, Walter MA, Buttyan R, Yi Y, Kaestner KH, Matusik RJ. FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype. Lab Invest. 2014 Jul; 94(7):726-39. PMID: 24840332; PMCID: PMC4451837.
    17. Grabowska MM, Elliott AD, DeGraff DJ, Anderson PD, Anumanthan G, Yamashita H, Sun Q, Friedman DB, Hachey DL, Yu X, Sheehan JH, Ahn JM, Raj GV, Piston DW, Gronostajski RM, Matusik RJ. NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. Mol Endocrinol. 2014 Jun; 28(6):949-64. PMID: 24801505; PMCID: PMC4042066.
    18. Akram ON, DeGraff DJ, Sheehan JH, Tilley WD, Matusik RJ, Ahn JM, Raj GV. Tailoring peptidomimetics for targeting protein-protein interactions. Mol Cancer Res. 2014 Jul; 12(7):967-78. PMID: 24642350.
      View in: PubMed
    19. Xiang Y, Qiu Q, Jiang M, Jin R, Lehmann BD, Strand DW, Jovanovic B, DeGraff DJ, Zheng Y, Yousif DA, Simmons CQ, Case TC, Yi J, Cates JM, Virostko J, He X, Jin X, Hayward SW, Matusik RJ, George AL, Yi Y. SPARCL1 suppresses metastasis in prostate cancer. Mol Oncol. 2013 Dec; 7(6):1019-30. PMID: 23916135; PMCID: PMC3838491.
    20. Choudhary S, Hegde P, Pruitt JR, Sielecki TM, Choudhary D, Scarpato K, Degraff DJ, Pilbeam CC, Taylor JA. Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis. Carcinogenesis. 2013 Dec; 34(12):2891-9. PMID: 23825153; PMCID: PMC3845890.
    21. Majumdar S, Gong EM, Di Vizio D, Dreyfuss J, Degraff DJ, Hager MH, Park PJ, Bellmunt J, Matusik RJ, Rosenberg JE, Adam RM. Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior. Neoplasia. 2013 Jul; 15(7):749-60. PMID: 23814487; PMCID: PMC3689238.
    22. Jin R, Sterling JA, Edwards JR, DeGraff DJ, Lee C, Park SI, Matusik RJ. Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS One. 2013; 8(4):e60983. PMID: 23577181; PMCID: PMC3618119.
    23. DeGraff DJ, Robinson VL, Shah JB, Brandt WD, Sonpavde G, Kang Y, Liebert M, Wu XR, Taylor JA. Current preclinical models for the advancement of translational bladder cancer research. Mol Cancer Ther. 2013 Feb; 12(2):121-30. PMID: 23269072.
      View in: PubMed
    24. Strand DW, DeGraff DJ, Jiang M, Sameni M, Franco OE, Love HD, Hayward WJ, Lin-Tsai O, Wang AY, Cates JM, Sloane BF, Matusik RJ, Hayward SW. Deficiency in metabolic regulators PPAR? and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. Am J Pathol. 2013 Feb; 182(2):449-59. PMID: 23219716; PMCID: PMC3562729.
    25. DeGraff DJ, Matusik RJ. Gender specific differences in bladder cancer. J Urol. 2012 Jul; 188(1):10-1. PMID: 22583637.
      View in: PubMed
    26. DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, Yu X, Smolkin ME, Chang SS, Cookson MS, Herrick MK, Shariat SF, Steinberg GD, Frierson HF, Wu XR, Theodorescu D, Matusik RJ. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012; 7(5):e36669. PMID: 22590586; PMCID: PMC3349679.
    27. DeGraff DJ, Cates JM, Mauney JR, Clark PE, Matusik RJ, Adam RM. When urothelial differentiation pathways go wrong: implications for bladder cancer development and progression. Urol Oncol. 2013 Aug; 31(6):802-11. PMID: 21924649; PMCID: PMC4886548.
    28. DeGraff DJ, Clark PE. Detection of tumor cells in the bone offers independent prognostic value in bladder cancer patients: the clinical and basic science perspective. Eur Urol. 2011 Aug; 60(2):239-40. PMID: 21195537.
      View in: PubMed
    29. Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ. Wnt/ß-catenin activation promotes prostate tumor progression in a mouse model. Oncogene. 2011 Apr 21; 30(16):1868-79. PMID: 21151173; PMCID: PMC3081383.
    30. Zhang J, Gao N, DeGraff DJ, Yu X, Sun Q, Case TC, Kasper S, Matusik RJ. Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression. Prostate. 2010 Jun 15; 70(9):934-51. PMID: 20209642; PMCID: PMC3712623.
    31. Chen Q, DeGraff DJ, Sikes RA. The developmental expression profile of PAX2 in the murine prostate. Prostate. 2010 May 01; 70(6):654-65. PMID: 20017165.
      View in: PubMed
    32. Degraff DJ, Aguiar AA, Chen Q, Adams LK, Williams BJ, Sikes RA. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells. Am J Transl Res. 2010 Mar 06; 2(2):200-8. PMID: 20407609; PMCID: PMC2855632.
    33. DeGraff DJ. Novel use of a combined artificial intelligence approach to identify patients with noninvasive urothelial cell carcinoma of the urinary bladder who are at greatest risk for progression to muscle-invasive disease: a step forward. Eur Urol. 2010 Mar; 57(3):407-8; discussion 408-9. PMID: 19945780.
      View in: PubMed
    34. Sun Q, Yu X, Degraff DJ, Matusik RJ. Upstream stimulatory factor 2, a novel FoxA1-interacting protein, is involved in prostate-specific gene expression. Mol Endocrinol. 2009 Dec; 23(12):2038-47. PMID: 19846536; PMCID: PMC2796152.
    35. Degraff DJ, Aguiar AA, Sikes RA. Disease evidence for IGFBP-2 as a key player in prostate cancer progression and development of osteosclerotic lesions. Am J Transl Res. 2009 Jan 20; 1(2):115-30. PMID: 19956425; PMCID: PMC2776314.
    36. Degraff DJ, Malik M, Chen Q, Miyako K, Rejto L, Aguiar AA, Bancroft DR, Cohen P, Sikes RA. Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model. J Cell Physiol. 2007 Oct; 213(1):261-8. PMID: 17492783.
      View in: PubMed
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