The primary goal of this proposal is to develop and test innovative nanoparticles to systemically deliver novel therapy (short hairpin or shRNA) in preclinical models for pancreatic cancer. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors accounting for >150,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how to block metastatic progression in PDACs. We are studying the molecular pathways that lead to tumor progression in PDAC. Our focus is the HMGA1 oncogene, which encodes the HMGA1a and HMGA1b chromatin remodeling proteins. HMGA1 proteins regulate gene expression by altering chromatin structure. My laboratory was the first to discover that HMGA1 functions as a potent oncogene in cultured cells and transgenic mice. We also found that inhibiting HMGA1 expression blocks oncogenic and cancer stem cell properties. Recently published studies from our group and others demonstrate that HMGA1 is overexpressed in >90% of primary, human PDACs, with highest levels in invasive, metastatic tumors, but no expression in precursor lesions or normal pancreas. Moreover, we found that HMGA1 protein levels are positively correlated with poor differentiation status and decreased survival. Knock-down of HMGA1 blocks multiple oncogenic and stem cell properties, including anchorage-independent cell growth, migration, invasion, 3-dimensional sphere formation in vitro and metastatic progression in murine models of PDAC. These findings indicate that HMGA1 promotes tumor progression in PDAC. Strikingly, our recent studies show that knock-down of HMGA1 with shRNA reprograms cancer cell lines from highly invasive, mesenchymal-like cells to noninvasive, epithelial-like cells by down-regulating transcriptional networks important in stem cells and tumor progression. Knock-down of HMGA1 also enhances sensitivity to cytotoxic therapy. Our co-investigators, Drs. Hanes and Maitra, have recently pioneered novel approaches to systemically deliver plasmid nanoparticles (NPs) with effective and sustained changes in gene expression in preclinical models. Based on these exciting results, we hypothesize that: 1.) HMGA1 drives tumor progression in PDAC and could serve as a target in therapy, and, 2.) shRNA NPs will block HMGA1 expression and reprogram PDAC cells into less aggressive cells that respond to therapy. Here, we propose to test these hypotheses using our unique resources and expertise with the following Specific Aims: 1.) To determine if inducible shRNA to HMGA1 reprograms PDAC cells into noninvasive, therapy-responsive cells in our preclinical models, and, 2.) To develop NP technology to deliver HMGA1 shRNA in preclinical models of PDAC. We will test shRNA delivery using our NPs that have been optimized for delivery and efficiency by altering diameter, shape, lipid content, and other biophysical properties. If successful, our studies should provide a new paradigm for the treatment of PDAC and improve outcomes for patients.