Pestell Lab 

 

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.


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;


SELECTED PUBLICATIONS


Shtutman, M., Zhurinsky, J., Simcha, I., Albanese, C., D'Amico, M., Pestell, R.G., and Ben-Ze'ev, A., The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.Proc Natl Acad Sci U S A. 1999 May 11; 96(10): p. 5522-7.

Fan, S., Wang, J., Yuan, R., Ma, Y., Meng, Q., Erdos, M.R., Pestell, R.G., Yuan, F., Auborn, K.J., Goldberg, I.D., and Rosen, E.M., BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999 May 21; 284(5418): p. 1354-6.

Bromberg, J.F., Wrzeszczynska, M.H., Devgan, G., Zhao, Y., Pestell, R.G., Albanese, C., and Darnell, J.E., Jr., Stat3 as an oncogene. Cell. 1999 Aug 6; 98(3): p. 295-303.

Lin, S.Y., Xia, W., Wang, J.C., Kwong, K.Y., Spohn, B., Wen, Y., Pestell, R.G., and Hung, M.C., Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A. 2000 Apr 11; 97(8): p. 4262-6.

Tazebay, U.H., Wapnir, I.L., Levy, O., Dohan, O., Zuckier, L.S., Zhao, Q.H., Deng, H.F., Amenta, P.S., Fineberg, S., Pestell, R.G., and Carrasco, N., The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med. 2000 Aug; 6(8): p. 871-8.

Sampson, E.M., Haque, Z.K., Ku, M.C., Tevosian, S.G., Albanese, C., Pestell, R.G., Paulson, K.E., and Yee, A.S., Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1. EMBO J. 2001 Aug 15; 20(16): p. 4500-11.

Tanaka, H., Matsumura, I., Ezoe, S., Satoh, Y., Sakamaki, T., Albanese, C., Machii, T., Pestell, R.G., and Kanakura, Y., E2F1 and c-Myc potentiate apoptosis through inhibition of NF-κB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell. 2002 May; 9(5): p. 1017-29.

Huang, E., Ishida, S., Pittman, J., Dressman, H., Bild, A., Kloos, M., D'Amico, M., Pestell, R.G., West, M., and Nevins, J.R., Gene expression phenotypic models that predict the activity of oncogenic pathways. Nat Genet. 2003 Jun; 34(2): p. 226-30.

Rowlands, T.M., Pechenkina, I.V., Hatsell, S.J., Pestell, R.G., and Cowin, P., Dissecting the roles of beta-catenin and cyclin D1 during mammary development and neoplasia. Proc Natl Acad Sci U S A. 2003 Sep 30; 100(20): p. 11400-5.

Iyengar, P., Espina, V., Williams, T.W., Lin, Y., Berry, D., Jelicks, L.A., Lee, H., Temple, K., Graves, R., Pollard, J., Chopra, N., Russell, R.G., Sasisekharan, R., Trock, B.J., Lippman, M., Calvert, V.S., Petricoin, E.F., 3rd, Liotta, L., Dadachova, E., Pestell, R.G., Lisanti, M.P., Bonaldo, P., and Scherer, P.E., Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest. 2005 May; 115(5): p. 1163-76.

Yang, Y., Stopka, T., Golestaneh, N., Wang, Y., Wu, K., Li, A., Chauhan, B.K., Gao, C.Y., Cveklova, K., Duncan, M.K., Pestell, R.G., Chepelinsky, A.B., Skoultchi, A.I., and Cvekl, A., Regulation of alphaA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin. EMBO J. 2006 May 17; 25(10): p. 2107-18.

Wang, C., Li, Z., Lu, Y., Du, R., Katiyar, S., Yang, J., Fu, M., Leader, J.E., Quong, A., Novikoff, P.M., and Pestell, R.G., Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci U S A. 2006 Aug 1; 103(31): p. 11567-72.

Ju, X., Katiyar, S., Wang, C., Liu, M., Jiao, X., Li, S., Zhou, J., Turner, J., Lisanti, M.P., Russell, R.G., Mueller, S.C., Ojeifo, J., Chen, W.S., Hay, N., and Pestell, R.G.,Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci U S A. 2007 May 1; 104(18): p. 7438-43.

Wu, K., Katiyar, S., Li, A., Liu, M., Ju, X., Popov, V.M., Jiao, X., Lisanti, M.P., Casola, A., and Pestell, R.G., Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8. Proc Natl Acad Sci U S A. 2008 May 13; 105(19): p. 6924-9.

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.

Zhou, J., Wang, C., Wang, Z., Dampier, W., Wu, K., Casimiro, M.C., Chepelev, I., Popov, V.M., Quong, A., Tozeren, A., Zhao, K., Lisanti, M.P., and Pestell, R.G.,Attenuation of Forkhead signaling by the retinal determination factor DACH1. Proc Natl Acad Sci U S A. 2010 Apr 13; 107(15): p. 6864-9.

Yu, Z., Willmarth, N.E., Zhou, J., Katiyar, S., Wang, M., Liu, Y., McCue, P.A., Quong, A.A., Lisanti, M.P., and Pestell, R.G., microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8231-6. Epub 2010 Apr 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.

Yu Z, Wang L, Wang C, Ju X, Wang M, Chen K, Loro E, Wu K, Casimiro MC, Gormley M, Ertel A, Fortina P, Tozeren A, Liu Z, Chen Y, Pestell RG. Cyclin D1 Induction of Dicer Governs MicroRNA Processing and Expression in Breast Cancer. Nat Commun. 2013 Nov 29;4:2812. doi: 10.1038/ncomms3812.

Zhang J, Wang C, Chen X, Takada M, Fan C, Zheng X, Wen H, Liu Y, Pestell RG, Aird KM, Kaelin Jr W, Liu XS, Zhang Q.  EgIN2 Associates, with the NRF1-PGC1Complex and Controls Mitochondrial Function in Breast Cancer. EMBO J 2015 Oct 22. pii: e201591437