Photo of Randolph Watnick,  PhD

Randolph Watnick, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2427


randy.watnick@childrens.harvard.edu

Randolph Watnick, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Surgery, Harvard Medical School
  • Research Associate, Vascular Biology Program, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

One of the major obstacles to effectively treating cancer is the development of drug resistance, due to the tremendous genomic instability present in virtually all tumors. In addition to resistance to therapy, tumors are also to evade the immune system by presenting “self” makers on the cell surface. One example of such a “self” marker is CD47, which binds SIRPα on macrophages and prevents phagocytosis, essentially acting as a “do not eat me” signal. CD47 is also a receptor for the anti-tumorigenic protein thrombospondin-1 (Tsp-1) and binding of Tsp-1 to CD47 blocks the interaction with SIRPα and promotes macrophage-mediated cell killing. In fact, Tsp-1 expression is normally down-regulated in tumor cells via activation of signaling pathways or constitutive activation of transcription factors and its down-regulation has been shown to be a mechanism of acquiring resistance to taxanes. However, these pathways are generally not mutated in the cells that comprise the tumor microenvironment. This presents a novel opportunity to attack the tumor by targeting the microenvironment.

Through a functional proteomic screen we have identified tumor-secreted proteins that modulate Tsp-1 expression in the tumor microenvironment. Specifically, the cells in which Tsp-1 is most strongly modulated are bone marrow derived myeloid suppressor cells (MDSCs) and macrophages. These cells are normally coopted by the tumor to stimulate growth and metastasis. In fact, through our screen, we have identified a protein, PRSS2, secreted by highly metastatic breast and prostate cancer cells that represses Tsp-1 expression in the microenvironment, and are in the process of developing a therapeutic antibody to block its activity.

Moreover, we have identified a protein, prosaposin, which stimulates Tsp-1 expression and converts these bone marrow derived cells into anti-tumorigenic agents. Based on these findings we developed a peptide derived from prosaposin that retains the Tsp-1 stimulating activity of the full-length protein. We have demonstrated that the prosaposin peptide is able to regress tumor growth in animal models at both the primary and metastatic sites when administered in a systemic manner. As a result of these findings, we are in the process of developing the prosaposin peptide as a therapeutic agent to treat multiple types of cancer, based on the expression of CD47.

Strikingly, we have found, through a multivariate analysis of over 250 prostate and endometrial cancer patients that prosaposin expression correlates with patient survival better than any other currently used prognostic marker. As such, we examined whether prosaposin expression, or the lack thereof, mediated drug resistance. To that end we examined multiple matched drug-sensitive (parental) and drug-resistant tumor cell lines and found that in all cases drug-resistant cells expressed significantly lower levels of prosaposin. Thus, repression of prosaposin could represent a novel method of acquiring drug resistance.

Publications from Harvard Catalyst Profiles

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  • 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; 8:329ra34. PubMed
  • 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 2015. PubMed
  • 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; 29:662-70. PubMed
  • 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; 111:1521-6. PubMed
  • 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. 2013; 3:578-89. PubMed
  • 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; 106:12115-20. PubMed
  • Kang SY, Watnick RS. Regulation of tumor dormancy as a function of tumor-mediated paracrine regulation of stromal Tsp-1 and VEGF expression. APMIS ; 116:638-47. PubMed