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Related Research Units

Vascular Biology Program Research

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.

Research Background

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

  1. Assessing CD36 and CD47 expression levels in solid tumor indications to stratify patients for VT1021 treatment. NPJ Precis Oncol. 2024 Dec 03; 8(1):278. View Abstract
  2. Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors. Commun Med (Lond). 2024 May 21; 4(1):95. View Abstract
  3. First-in-human phase I dose escalation trial of the first-in-class tumor microenvironment modulator VT1021 in advanced solid tumors. Commun Med (Lond). 2024 Jan 13; 4(1):10. View Abstract
  4. PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression. Nat Commun. 2022 12 27; 13(1):7959. View Abstract
  5. A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor. PLoS One. 2018; 13(12):e0208579. View Abstract
  6. Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy. Angiogenesis. 2018 11; 21(4):837-848. View Abstract
  7. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med. 2016 Mar 09; 8(329):329ra34. View Abstract
  8. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood. 2016 Feb 18; 127(7):921-6. View Abstract
  9. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene. 2015 May 28; 34(22):2949-50. View Abstract
  10. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70. View Abstract
  11. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene. 2015 May 28; 34(22):2823-35. View Abstract
  12. Spontaneous reversion of the angiogenic phenotype to a nonangiogenic and dormant state in human tumors. Mol Cancer Res. 2014 May; 12(5):754-64. View Abstract
  13. 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. View Abstract
  14. 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. View Abstract
  15. Retraction. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2013 Jan 14; 23(1):129. View Abstract
  16. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb Perspect Med. 2012 Dec 01; 2(12):a006676. View Abstract
  17. 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. View Abstract
  18. 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. View Abstract
  19. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008 Jul 11; 134(1):62-73. View Abstract
  20. 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. View Abstract
  21. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst. 2006 Mar 01; 98(5):316-25. View Abstract
  22. 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 04; 102(1):175-9. View Abstract
  23. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2003 Mar; 3(3):219-31. View Abstract
  24. 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. View Abstract
  25. Binding of transcription termination protein nun to nascent RNA and template DNA. Science. 1999 Dec 17; 286(5448):2337-9. View Abstract
  26. 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. View Abstract

Contact Randolph Watnick

Phone: 617-919-2427
Fax: 617-730-0231
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