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Mechanisms of Pancreatic Cancer Inhibition by SPARC

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Pancreatic cancer is one of the most aggressive human malignancies. In most patients it is diagnosed at advanced stages not amenable by surgery, and it is highly resistant to conventional treatments. With median survival less than 1 year and 5-year survival less than 5%1, the need for additional treatment strategies is high. Severe desmoplasia is a hallmark of pancreatic cancer, and the tumor microenvironment has been shown to play an essential role in the progression and chemoresistance of this disease. Thus, the tumor microenvironment is a promising therapeutic target for pancreatic cancer. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular protein that modulates interactions between cells and their environment2,3. We have shown that SPARC modifies the assembly and organization of the extracellular matrix4 by functioning as an extracellular chaperone5. Our studies have demonstrated that SPARC inhibits the growth of several types of cancers (6,7 and Preliminary Studies). We have established that the anti-tumor properties of SPARC are mediated in part, by its angiogenesis inhibition6 and by blockade of fibroblast activation4, two major features of cancer-induced desmoplasia. Using structure-functional studies, we have shown that SPARC peptides corresponding to the highly conserved follistatin domain have potent anti- angiogenic activity8,9 and inhibit the growth of neuroblastoma9, pancreatic, lung, and breast cancers (Preliminary Studies). Thus SPARC has tumor suppressor functions in a broad range of neoplasms. Based on these data, we hypothesize that by interacting with matrix and stromal proteins, SPARC inhibits the growth of pancreatic cancer by blocking desmoplastic changes, and creating a more "normal" microenvironment that is non-permissive for tumor growth. The mechanisms by which SPARC modulates the tumor microenvironment and inhibits tumor growth remain largely unknown. We propose elucidating the mechanism using a unique systematic approach, developed by Dr. He, the co-PI on this grant10-12, to isolate proteins that are targeted by SPARC in pancreatic tumor tissue. Established interactions will be validated by co-expression and co-precipitation with SPARC. The functional significance of validated targets will be tested by down-regulation with shRNA and the ability to counteract anti-tumor properties of SPARC in a mouse xenograft model.

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