PSU Profiles
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Last Name
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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

 Biography 
 awards and honors
2013 - NIH Pathway to Independence Award (K99/R00)
2013 - New Investigator Award
2010 - Postdoctoral Fellowship
2011 - Travel award
2009 - Postdoctoral Fellowship
2009 - Travel award
2009 - Travel award
2009 - John Quale Travel award
2009 - Trainee, Integrated Biological Systems Training in Oncology
2008 - Trainee, Multidisciplinary training in Molecular Endocrinology
2007 - Trainee, Integrative Graduate Education and Research (IGERT)
2006 - Travel award
2004 - University Graduate Fellowship
2002 - Reisher Scholarship Recipient

 Overview 
 overview
Title:
Assistant Professor of Pathology
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.


 Bibliographic 
 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.
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  1. 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.
    View in: PubMed
  2. 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.
    View in: PubMed
  3. 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.
    View in: PubMed
  4. 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.
    View in: PubMed
  5. 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.
    View in: PubMed
  6. 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.
    View in: PubMed
  7. 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.
    View in: PubMed
  8. 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.
    View in: PubMed
  9. 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.
    View in: PubMed
  10. 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.
    View in: PubMed
  11. 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.
    View in: PubMed
  12. 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.
    View in: PubMed
  13. DeGraff DJ, Matusik RJ. Gender specific differences in bladder cancer. J Urol. 2012 Jul; 188(1):10-1.
    View in: PubMed
  14. 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.
    View in: PubMed
  15. 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.
    View in: PubMed
  16. 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.
    View in: PubMed
  17. 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.
    View in: PubMed
  18. 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.
    View in: PubMed
  19. Chen Q, DeGraff DJ, Sikes RA. The developmental expression profile of PAX2 in the murine prostate. Prostate. 2010 May 1; 70(6):654-65.
    View in: PubMed
  20. 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; 2(2):200-8.
    View in: PubMed
  21. 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.
    View in: PubMed
  22. 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.
    View in: PubMed
  23. 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; 1(2):115-30.
    View in: PubMed
  24. 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.
    View in: PubMed
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