Pancreatic ductal adenocarcinomas (PDACs) overexpress all three transforming growth factor beta (TGF-2) isoforms and inhibitory Smad7, and frequently harbor Kras mutations. High TGF-2 levels in PDAC correlate with disease progression, yet Smad7 and oncogenic Kras generally block TGF-2-mediated Smad2 and Smad3 nuclear translocation, implicating dysregulated TGF-2 signaling in PDAC. In this proposal we will test the hypothesis that Smad7 overexpression contributes to pancreatic cancer progression and metastasis by modulating TGF-2 actions in cancer cells in a manner that promotes their growth, survival and chemoresistance, and that Smad7 synergizes with mutated and constitutively active Kras to promote pancreatic cancer progression and metastasis. Three approaches will be used to test this hypothesis. First, the consequences of Smad7 overexpression in three PDAC cell lines will be determined in vitro with respect to biological actions and signaling, and in athymic mice with respect to tumor formation, growth, invasion, metastasis, angiogenesis and apoptosis. Second, mice that express transcriptionally silenced (LoxP-Stop-LoxP) Smad7 in Nestin-expressing cells will be generated for breeding with mice expressing Cre recombinase under control of the Pdx1 promoter (Pdx1-Cre), in order to assess the role of Smad7 alone in the initiation and progression of pancreatic cancer. Animals carrying both Nestin-LSL-Smad7 and LSL- KrasG12D alleles will then be bred to the Pdx1-Cre mice in order to look for in vivo synergy between Smad7 and mutated Kras. Only the triple compound mutants will have activated Kras expressed in the whole pancreas while Smad7 expression will overlap only with the Nestin-expressing subpopulation. Third, since high Smad7 levels lead to the functional inactivation of pRb, mice that express Rb with a floxed Stop cassette in the introns flanking exon 19 (LSL-Rb) will be bred with mice carrying LSL-KrasG12D alleles and Pdx1- Cre, in order to determine whether mutated Rb mimics the in vivo actions of Smad7. Pancreata from control and mutant mice in aims II and III will be analyzed histologically at defined time points, and the consequences on pancreatic intraepithelial neoplasia (PanIN), cancer formation and altered TGF-2 signaling will be determined. Project Narrative: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in adults in the United States, with mortality virtually equaling incidence. This disease may be an even more serious problem in the future since its incidence increases after age 50 and the general population in the United States is aging. This proposal aims to provide an improved understanding of the biological causes that contribute to this disease aggressiveness, with the ultimate goal of devising better diagnostic and therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-ONC-K (03))
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Salnikow, Konstantin
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Gore, A Jesse; Deitz, Samantha L; Palam, Lakshmi Reddy et al. (2014) Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-* to promote proliferation. J Clin Invest 124:338-52
Ueda, J; Matsuda, Y; Yamahatsu, K et al. (2014) Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene 33:4485-95
Korc, Murray (2014) p38 MAPK in pancreatic cancer: finding a protective needle in the haystack. Clin Cancer Res 20:5866-8
Slee, Roger B; Grimes, Brenda R; Bansal, Ruchi et al. (2014) Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715. Mol Cancer Ther 13:307-15
Ouyang, H; Gore, J; Deitz, S et al. (2014) microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-* actions. Oncogene 33:4664-74
Liu, Fang; Gore, A Jesse; Wilson, Julie L et al. (2014) DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine. PLoS One 9:e84982
Matsuda, Yoko; Yoshimura, Hisashi; Ueda, Junji et al. (2014) Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2R?(null) (NOG) mice. Am J Pathol 184:674-85
Norris, A M; Gore, A; Balboni, A et al. (2013) AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 32:3867-76
Sempere, Lorenzo F; Korc, Murray (2013) A method for conducting highly sensitive microRNA in situ hybridization and immunohistochemical analysis in pancreatic cancer. Methods Mol Biol 980:43-59
Kramer-Marek, Gabriela; Gore, Jesse; Korc, Murray (2013) Molecular imaging in pancreatic cancer--a roadmap for therapeutic decisions. Cancer Lett 341:132-8

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