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Richard G. Pestell, M.D., Ph.D.

status

Dr. Richard Pestell is currently the President of the Pennsylvania Cancer and Regenerative Medicine Research Center, a part of the Baruch S. Blumberg Institute in Doylestown, Pennsylvania.  He previously held the position of Director of the Sidney Kimmel Cancer Center, Executive Vice President Thomas Jefferson University, Chairman of the Dept. of Cancer Biology, Thomas Jefferson University, Philadelphia, PA

 

background

Originally from Perth, Australia, Dr. Pestell holds a medical degree from the University of Western Australia, and a Ph.D. from the University of Melbourne, Howard Florey Institute. He conducted clinical training in oncology and endocrinology and was inducted as a Fellow of the Royal Australian College of Physicians. His postdoctoral research at the Harvard School of Medicine and Massachusetts General Hospital with Dr. Larry Jameson focused on endocrine oncology. He completed his executive MBA from New York University Stern School of Business in 2011. He has received many awards for his research discoveries including elected membership to ASCI (American Society of Clinical Investigation), Elected Member, Royal Society of Medicine, the RD Wright Medallion, Elected Fellow, American Association for the Advancement of Science, the Eric Susman Prize in Medicine, Advance Global Australian Award (Biotechnology), a Doctor of Medical Sciences, HonorisCausa, from the University of Melbourne, and awards from Susan G. Komen (Light of Life award, Jamie Brooke Lieberman Award). He has several issued patents in biotechnology, diagnostics and cancer therapeutics.

 

Contributions to Science

Prostate cancer: As prostate cancer onset and progression involves the mune system we developed a metastatic murine model that recapitulates human prostate cancer, both geneticaly and epigenetically, and metastasizes to bones and brain in the muse.. We demonstrated that in human prostate cancer cells the abundance of cyclin D1 is induced by growth factors and siRNA to cyclin D1 reduced ErbB2-mediated DNA synthesis in LNCaP cells (Cancer Research, 2007; 67(9):4364-4372)., that cyclin D1 restrains EMT and promotes stem cell expanding gene expression in the prostate. This may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer (Cancer Research, 2014; Jan 15; 74(2):508-19).

Dach1 and Cancer. Dach1 was initially cloned as a gene governing eye development. Dr. Pestell has led in the field of Dach1 in tumorigenesis. Pestell was the first to show that Dach1 restrains tumor growth, that the abundance of Dach1 is reduced in human cancers and that Dach1 restrains stem cells through reprogramming an Oct/Nanog/EKLF pathway. He was the first to show Dach1 binds to non-canonical TF binding sites (c-Jun, Smad) and bind DNA directly to promote gene expression modules. He showed Dach1 is phosphorylated and acetylated and controls breast cancer epithelial cell growth and migration in vitro and in vivo.

Androgen and Nuclear receptor acetylation. Dr. Pestell was the first to show nuclear receptors including the androgen receptor, are acetylated, that acetylation regulates contact-independent growth, and that this event is rate-limiting in hormone signaling and that acetylation is a general mechanism conserved among diverse nuclear receptors regulating diverse biological processes. Dr. Pestell proved that a single residue acetylated in the nuclear receptor, converted a growth suppressor into a growth activator. There have been >19,300 publications on nuclear receptor acetylation since our original discovery.

Cancer Stem cells. The Pestell lab has defined the requirement for specific target genes in the formation of breast and prostate epithelial cancer stems cells using transgenic or inducible knockout mice (NFκB, p21CIP1, c-jun) and have defined distinct roles for cyclin D1 in polarity vs stem cell function. These transgenic animals have been shared widely with the research community.

Cyclin D1 non canonical functions governing gene expression. Dr. Pestell has been a pioneer in the understanding of cell-cycle control in cancer. He was the first to show that: 1) cyclins are direct transcriptional targets of oncogenic and tumor suppressor signals; 2) cyclin D1 expression is rate-limiting for oncogeneinduced breast tumor and colon growth in vivo; 3) cyclin D1 binds DNA to regulate gene expression and chromosomal instability; 4) cyclins interact with nuclear receptors and tumor suppressors; 5) cyclins regulate mitochondrial metabolism, cellular migration, the non-coding genome and its biogenesis;

 

Summary of Published Work (>615 published works with >53,000 citations): http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&term=Pestell%20R%2A&doptcmdl=DocSum

 

Selected Publications

1. Ju X, Ertel A, Casimiro MC, Yu Z, Meng H, McCue PA, Walters R, Fortina P, Lisanti MP, Pestell RG Novel oncogene-induced metastatic prostate cancer cell lines define human prostate cancer progression signatures. Cancer Res. 2013 Jan 15;73(2):978-89. doi: 10.1158/0008-5472.CAN-12-2133. Epub 2012 Nov 30. PMCID: PMC3561759.

2. Ju, X. and Casimiro, M.C., Gormley, M., Meng, H., Jiao, X., Katiyar, S., Crosariol, M., Chen, K., Wang, M., Quong, A.A., Lisanti MP, Ertel A, Pestell RG. Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint. Cancer Research. 2014 Jan 15; 74(2):508-19. PMCID: PMC3914674.

3. Casimiro, M.C., Ju, X., Gormley, M., Meng, H., Jiao, X., Katiyar, S., Crosariol, M., Chen, K., Wang, M., Quong, A.A., Lisanti MP, Ertel A, Pestell RG. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells. Cancer Research, 2016 Jan 15;76(2):329-38. PMCID:PMC4715975.

4. Ju X, Jiao X, Ertel A, Casimiro MC, Di Sante G, Deng S, Li Z, Di Rocco A, Zhan T, Hawkins A, Stoyanova T, Andò S, Fatatis A, Lisanti MP, Gomella LG, Languino LR, Pestell RG. v-Src oncogene induces Trop2 proteolytic cleavage. Cancer Res. 2016 Sep 15 PMID:27634768

5. Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin- 8.. Proc Natl Acad Sci USA. 2008 May 13;105(19):6924-9. PMCID: PMC2374551.

6. Zhou J, Wang C, Wang Z, Dampier W, Wu K, Casimiro MC, Chepelev I, Popov VM, Quong A, Tozeren A, Zhao K, Lisanti MP, Pestell RG. Attenuation of Forkhead signaling by the retinal determination factor DACH1. Proc Natl Acad Sci USA. 2010 Apr 13;107(15):6864-9. doi: 10.1073/pnas.1002746107. Epub 2010 Mar 29, PMCID: PMC2872468.

7. Chen K, Wu K, Wang L, Jiao X, Ju X, Li Z, Ertel A, Addya S, McCue P, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. The endogenous Cell-Fate Factor Dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a CXCL Signaling Module. Cancer Research. 2015 2015 May 15;75(10):1992-2004. PMID:25769723.

8. Ozcan L, Ghorpade D, Cristina de Sozua J, Chen K, Bessler M, Bagloo M, Schrope B, Pestell RG, Tabas, I. Hepatocyte DACH1 is Increased in Obesity Via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep. 2016 May 26. un 7;15(10):2214-25 PMID:27239042

9. Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem. 2000 Jul 7;275(27):20853- 60, PMCID: Identifier absent.

10. Wang, C., Fu, M., Angeletti, R.H., Siconolfi-Baez, L., Reutens, A.T., Albanese, C., Lisanti, M.P., Katzenellenbogen, B.S., Kato, S., Hopp, T., Fuqua, S.A., Lopez, G.N., Kushner, P.J., and Pestell, R.G., Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001 May 25; 276(21): p. 18375-83, PMCID: Identifier absent.

11. Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, Chang C, Hopp T, Fuqua SA, Jaffray E, Hay RT, Palvimo JJ, Jänne OA, Pestell RG. Androgen Receptor Acetylation Governs Transactivation and MEKK1-Induced Apoptosis Without Effecting In Vitro Sumoylation and transrepression Function. Mol Cell Biol. 2002 May;22(10):3373-88.

12. Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, Fan S, Rosen E, Palvimo JJ, Jänne OA, Muratoglu S, Avantaggiati ML, Pestell RG. Acetylation of the androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 2003 Dec;23(23):8563-75, PMCID: PMC262657

13. Liu, M., Casimiro, M.C., Wang, C., Shirley, L.A., Jiao, X., Katiyar, S., Ju, X., Li, Z., Yu, Z., Zhou, J., Johnson, M., Fortina, P., Hyslop, T., Windle, J.J., and Pestell, R.G., p21CIP1 attenuates Ras- and c-Mycdependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci USA. 2009 Nov 10; 106(45): p. 19035-9. PMCID: PMC2776463.

14. Genander, M., Halford, M.M., Xu, N.J., Eriksson, M., Yu, Z., Qiu, Z., Martling, A., Greicius, G., Thakar, S., Catchpole, T., Chumley, M.J., Zdunek, S., Wang, C., Holm, T., Goff, S.P., Pettersson, S., Pestell, R.G., Henkemeyer, M., and Frisen, J., Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 2009 Nov 13; 139(4): p. 679-92, PMCID: PMC2786256.

15. Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow, W-S., Wang, C.,Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-10473.,k, PMCID: PMC3010731.

16. Jiao , X., Katiyar, S., Willmarth, N.E., Liu, M., Ma, X., Flomenberg, N., Lisanti, M.P., and Pestell, R.G., cJun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem. 2010 Mar 12; 285(11): p. 8218-26. PMCID: PMC2832973.

17. Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 2000 Jan;20(2):672-83. PMCID: PMC85165.

18. Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG. Cyclin D1 governs adhesion and motility of macrophages. Mol Biol Cell. 2003 May;14(5):2005-15. Epub 2003 Feb 21. PMCID: PMC165093.

19. Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, Pestell RG. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci USA. 2006 Aug 1;103(31):11567-72. Epub 2006 Jul 24. PMCID: PMC1518800.

20. Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, Saria E, Papanikolaou A, Li Z, Wang C, Fortina P, Addya A, Tozeren A, Knudsen ES, Arnold A, Pestell RG. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Invest. 2012 Mar 1;122(3):833-43. doi: 10.1172/JCI60256. Epub 2012 Feb 6. PMCID: PMC3287228.