Research

LIke ThisLIke ThisLIke This

Randolph Watnick, PhD

Randolph Watnick
Program:
Vascular Biology Program
Department:
Surgery Research
Hospital Title:
Research Associate
Academic Title:
Assistant Professor Department of Surgery, Harvard Medical School
Contact:
617-919-2427

Research Overview

One of the rate limiting steps in the progression of cancer is the acquisition of angiogenicity. In fact, the induction of angiogenesis not only allows the primary tumor to grow beyond the size limitation of 2mm, imposed by the diffusion limit of oxygen, but also provides a conduit through which the tumors can travel to and colonize distant organs. Once the tumor cells arrive at the metastatic site they must also induce neovascualarization in order to grow beyond the 2mm size constraint. Often, however, the metastasis remains dormant and does not progress beyond this size for months or years following its colonization.

The role of the tumor-associated stroma has been demonstrated to be of significant importance to both breast and prostate cancer formation, perhaps moreso than in other cancers. It has been demonstrated, for instance, that stromal fibroblasts isolated from a prostate tumor induce tumor formation of immortal but non-transformed prostate epithelial cells when the mixture is injected orthotopically into nude mice. Thus it would appear that prostate cancer cells have a strong dependence on their surrounding stroma. More importantly, prostate cancer cells are able to alter their surrounding stromal fibroblasts to enhance tumor growth. As such, we study the regulation of angiogenesis, proliferation and motility in both epithelial cells and fibroblasts. We have identified a novel suppressor of metastasis, Prosaposin, which acts both locally and distally by stimulating the expression/activity of p53, which then stimulates the expression of Tsp-1. Significantly, Prosaposin also inhibits metastasis when administered in a systemic fashion thus making it a potential therapeutic agent to stem the metastatic dissemination of human tumors.

About Randolph Watnick

Dr. Watnick received his Bachelor of Science degree from Trinity College, in Hartford, CT, in 1993. He went on to earn a Ph.D. in Biochemistry and Molecular Biophysics from Columbia University in 1999. At Columbia, Dr. Watnick received a pre-doctoral fellowship from the National Eye Institute and was awarded the Samuel and Lewis Rover Award for outstanding research in Biochemistry and Molecular Biophysics. After receiving his Ph.D., Dr. Watnick continued his training as a post-doctoral fellow in the laboratory of Dr. Robert Weinberg at the Whitehead Institute for Biomedical Research. During this time Dr. Watnick was awarded a Damon Runyon post-doctoral fellowship. In 2003 Dr. Watnick was appointed an Assistant Professor in the Department of Surgery at Harvard Medical School and a Research Associate in the Vascular Biology Program at Boston Children's Hospital.

Publications

Publications powered by Harvard Catalyst Profiles
  1. Wang S, Blois A, El Rayes T, Liu JF, Hirsch MS, Gravdal K, Palakurthi S, Bielenberg DR, Akslen LA, Drapkin R, Mittal V, Watnick RS. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med. 2016 Mar 9; 8(329):329ra34.
  2. Machlus KR, Johnson KE, Kulenthirarajan R, Forward JA, Tippy MD, Soussou TS, El-Husayni SH, Wu SK, Wang S, Watnick RS, Italiano JE, Battinelli EM. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood. 2016 Feb 18; 127(7):921-6.
  3. Watnick RS, Rodriguez RK, Wang S, Blois AL, Rangarajan A, Ince T, Weinberg RA. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene. 2015 May 28; 34(22):2949-50.
  4. Watnick RS, Rodriguez RK, Wang S, Blois AL, Rangarajan A, Ince T, Weinberg RA. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene. 2015 May 28; 34(22):2823-35.
  5. Rogers MS, Novak K, Zurakowski D, Cryan LM, Blois A, Lifshits E, Bø TH, Oyan AM, Bender ER, Lampa M, Kang SY, Naxerova K, Kalland KH, Straume O, Akslen LA, Watnick RS, Folkman J, Naumov GN. Spontaneous reversion of the angiogenic phenotype to a nonangiogenic and dormant state in human tumors. Mol Cancer Res. 2014 May; 12(5):754-64.
  6. Li W, Ai N, Wang S, Bhattacharya N, Vrbanac V, Collins M, Signoretti S, Hu Y, Boyce FM, Gravdal K, Halvorsen OJ, Nalwoga H, Akslen LA, Harlow E, Watnick RS. GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci U S A. 2014 Jan 28; 111(4):1521-6.
  7. Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D, Ryu S, Joshi N, Bielenberg D, Lee SB, Haukaas SA, Gravdal K, Halvorsen OJ, Akslen LA, Watnick RS, Mittal V. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 2013 May; 3(5):578-89.
  8. Retraction. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2013 Jan 14; 23(1):129.
  9. Watnick RS. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb Perspect Med. 2012 Dec; 2(12):a006676.
  10. Straume O, Shimamura T, Lampa MJ, Carretero J, Øyan AM, Jia D, Borgman CL, Soucheray M, Downing SR, Short SM, Kang SY, Wang S, Chen L, Collett K, Bachmann I, Wong KK, Shapiro GI, Kalland KH, Folkman J, Watnick RS, Akslen LA, Naumov GN. Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer. Proc Natl Acad Sci U S A. 2012 May 29; 109(22):8699-704.
  11. Show all
  12. Kang SY, Halvorsen OJ, Gravdal K, Bhattacharya N, Lee JM, Liu NW, Johnston BT, Johnston AB, Haukaas SA, Aamodt K, Yoo S, Akslen LA, Watnick RS. Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1. Proc Natl Acad Sci U S A. 2009 Jul 21; 106(29):12115-20.
  13. Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, Liu A, Miu K, Watnick RS, Reinhardt F, McAllister SS, Jacks T, Weinberg RA. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008 Jul 11; 134(1):62-73.
  14. Kang SY, Watnick RS. Regulation of tumor dormancy as a function of tumor-mediated paracrine regulation of stromal Tsp-1 and VEGF expression. APMIS. 2008 Jul-Aug; 116(7-8):638-47.
  15. Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, Watnick RS, Straume O, Akslen LA, Folkman J, Almog N. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst. 2006 Mar 1; 98(5):316-25.
  16. Cerimele F, Battle T, Lynch R, Frank DA, Murad E, Cohen C, Macaron N, Sixbey J, Smith K, Watnick RS, Eliopoulos A, Shehata B, Arbiser JL. Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma. Proc Natl Acad Sci U S A. 2005 Jan 4; 102(1):175-9.
  17. Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2003 Mar; 3(3):219-31.
  18. Watnick RS, Herring SC, Palmer AG, Gottesman ME. The carboxyl terminus of phage HK022 Nun includes a novel zinc-binding motif and a tryptophan required for transcription termination. Genes Dev. 2000 Mar 15; 14(6):731-9.
  19. Watnick RS, Gottesman ME. Binding of transcription termination protein nun to nascent RNA and template DNA. Science. 1999 Dec 17; 286(5448):2337-9.
  20. Watnick RS, Gottesman ME. Escherichia coli NusA is required for efficient RNA binding by phage HK022 nun protein. Proc Natl Acad Sci U S A. 1998 Feb 17; 95(4):1546-51.
  21. Adini I, Adini A, Bazinet L, Watnick RS, Bielenberg DR, D'Amato RJ. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70.
LIke ThisLIke ThisLIke This
Close