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Drug Discovery in Pancreatic Cancer pp 95–112Cite as

Zebrafish as a Biological System for Identifying and Validating Therapeutic Targets and Compounds

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Abstract

Pancreatic cancer is a great oncologic challenge. Significant progress has been made in understanding the molecular genetics for transformation of pancreatic epithelia into pre-malignant neoplasia and eventually invasive carcinoma. In spite of these advances, effective treatment is still lacking, and the prognosis of most patients diagnosed with pancreatic cancer is dismal. Molecularly targeted agents show great potential for improving treatment in pancreatic cancer cells and animal models. However, translation of the preclinical studies into clinically useful drugs with meaningful benefits for the patients remains to be accomplished. Development of zebrafish models and application of innovative techniques will enable drug discovery for pancreatic cancer in a whole organism. The established models including wild-type zebrafish larvae, germ-line mutants, transgenics, and xenografts can be utilized to identify the genetic pathways and their interactions that control exocrine pancreatic development and cancer. Combined application of chemical genetic screens with radiographic imaging, nanoparticulate systems, and bioinformatics in the zebrafish models is expected to facilitate identification of drugs that specifically target the signaling networks in pancreatic cancer stem cells, and validation of candidate therapeutics by real-time monitoring of tumor growth. Ultimately, a systems-biology approach that applies the various techniques to the zebrafish models is predicted to lead to discovery of efficacious and safe drugs toward the goal of targeted and personalized therapy in pancreatic cancer.

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References

  • Amatruda JF, Shepard JL, Stern HM et al (2002) Zebrafish as a cancer model system. Cancer Cell 1:1–4

    Article  Google Scholar 

  • Berman DM, Karhadkar SS, Maitra A et al (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851

    Article  CAS  PubMed  Google Scholar 

  • Bloomston M, Frankel WL, Petrocca F et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Burgess S, Hopkins N (2001) Analysis of the zebrafish smoothened mutant reveals conserved and divergent function of hedgehog activity. Development 128:2385–2396

    CAS  PubMed  Google Scholar 

  • Chen J, Ruan H, Ng SM et al (2005a) Loss of function of def selectively up-regulates D113p53 expression to arrest expansion growth of digestive organs in zebrafish. Genes Dev 19:2900–2911

    Article  CAS  Google Scholar 

  • Chen PY, Manninga H, Slanchev K et al (2005b) The developmental miRNA profiles of zebrafish as determined by small RNA cloning. Genes Dev 19:1288–1293

    Article  CAS  Google Scholar 

  • Chen R, Yi EC, Donohoe S et al (2005c) Pancreatic cancer proteome: The proteins that underlie invasion, metastasis, and immunologic escape Gastroenterology 129:1187–1197

    Google Scholar 

  • Chun SG, Zhou W, Yee NS (2009) Combined targeting of histone deacetylases and hedgehog signaling enhances cytotoxicity in pancreatic cancer. Cancer Biol Ther 8: 1328–1339

    Article  Google Scholar 

  • Davuluri G, Gong W, Yusuff S et al (2008) Mutation of the zebrafish nucleoporin elys sensitizes tissue progenitors to replication stress. PLoS Genet 4:1–13

    Article  Google Scholar 

  • De La O JP, Emerson LL, Goodman JL et al (2008) Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA 105:18907–18912

    Article  Google Scholar 

  • Dong PDS, Provost E, Leach SD et al (2008) Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas. Genes Dev 22:1145–1450

    Google Scholar 

  • Esni F, Ghosh B, Biankin AV et al (2004) Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131:4213–4224

    Article  CAS  PubMed  Google Scholar 

  • Field HA, Dong PDS, Beis D et al (2003) Formation of the digestive system in zebrafish. II. Pancreas morphogenesis. Dev Biol 261:197–208

    Article  CAS  PubMed  Google Scholar 

  • Goessling W, North TE, Zon L (2007) Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors. Nat Methods 4:551–553

    Article  CAS  PubMed  Google Scholar 

  • Haberland M, Montgomery RL, Olson EN (2008) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42

    Article  Google Scholar 

  • Haldi M, Ton C, Seng WL et al (2006) Human melanoma cells transplanted into zebrafish proliferate, migrate, produce melanin, form masses and stimulate angiogenesis in zebrafish. Angiogenesis 9:139–151

    Article  PubMed  Google Scholar 

  • Hamilton F (1822) An account of the fishes found in the River Ganges and its branches. Archibald Constable and Company, Edinburgh and London, pp 1–405

    Google Scholar 

  • Haramis APG, Hurlstone A, Velden YVD et al (2006) Adenomatous polyposis coli-deficient zebrafish are susceptible to digestive tract neoplasia. EMBO 7:444–449

    CAS  Google Scholar 

  • Hong CC (2009) Large-scale small-molecule screen using zebrafish embryos. Methods Mol Biol 486:43–55

    Article  CAS  PubMed  Google Scholar 

  • Hruban RH, Goggins M, Parsons JL et al (2000) Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972

    CAS  PubMed  Google Scholar 

  • Itoh M, Kim C-H, Palardy G et al (2003) Mind Bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4:67–82

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Google Scholar 

  • Johnson SA, Dubeau L, Johnson DL (2008) Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J Biol Chem 283:19184–19191

    Article  CAS  PubMed  Google Scholar 

  • Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

    Article  CAS  PubMed  Google Scholar 

  • Koorstra J-BM, Hustinx SR, Offerhaus GJA et al (2008) Pancreatic carcinogenesis. Pancreatology 8:110–125

    Article  PubMed  Google Scholar 

  • Lam SH, Mathavan S, Tong Y et al (2008) Zebrafish Whole-Adult-Organism chemogenomics for large-scale predictive and discovery chemical biology. PLoS Genet 4:1–14

    Article  Google Scholar 

  • Le X, Langenau DM, Keefe MD et al (2007) Heat shock-inducible Cre/Lox approaches to induce diverse types of tumors and hyperplasia in transgenic zebrafish. Proc Natl Acad Sci USA 104:9410–9415

    Article  CAS  PubMed  Google Scholar 

  • Lee EJ, Gusev Y, Jiang J et al (2007) Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 120:1046–1054

    Article  CAS  PubMed  Google Scholar 

  • Lee LMJ, Seftor EA, Bonde G et al (2005) The fate of human malignant melanoma cells transplanted into zebrafish embryos: Assessment of migration and cell division in the absence of tumor formation. Dev Dyn 233:1560–1570

    Article  CAS  PubMed  Google Scholar 

  • Lin JW, Biankin AV, Horb ME et al (2004) Differential requirement for ptfla in endocrine and exocrine lineages of developing zebrafish pancreas. Dev Biol 270:474–486

    Article  CAS  PubMed  Google Scholar 

  • Lucitt MB, Price TS, Pizarro A et al (2008) Analysis of the zebrafish proteome during embryonic development. Mol Cell Proteomics 7:981–994

    Article  CAS  PubMed  Google Scholar 

  • Marshall L, Kenneth NS, White RJ (2008) Elevated tRNA(iMet) synthesis can drive cell proliferation and oncogenic transformation. Cell 133:78–89

    Article  CAS  PubMed  Google Scholar 

  • Matthews RP, Lorent K, Manoral-Mobias R et al (2009) TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish s-adenosylhomocysteine hydrolase. Development 136:865–875

    Article  Google Scholar 

  • Mayer AN, Fishman MC (2003) nil per os encodes a conserved RNA recognition motif protein required for morphogenesis and cytodifferentiation of digestive organs in zebrafish. Development 130:3917–3928

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto Y, Maitra A, Ghosh B et al (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565–576

    Article  CAS  PubMed  Google Scholar 

  • Mizgireuv IV, Revskoy SY (2006) Transplantable tumor lines generated in clonal zebrafish. Cancer Res 66:3120–3125

    Article  CAS  PubMed  Google Scholar 

  • Morton JP, Mongeau ME, Klimstra DS et al (2007) Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 104: 5103–3108

    Article  CAS  PubMed  Google Scholar 

  • Murphey RD, Zon LI (2006) Small molecule screening in the zebrafish. Methods 39:255–261

    Article  CAS  PubMed  Google Scholar 

  • Murtaugh LC (2008) The what, where, when and how of Wnt/β-catenin signaling in pancreas development. Organogenesis 4:81–86

    Article  PubMed  Google Scholar 

  • Nicole S, Ribatti D, Cotelli F et al (2007) Mammalian tumor xenografts induce neovascularization in zebrafish embryos. Cancer Res 67:2927–2931

    Article  Google Scholar 

  • Noel ES, Casal-Sneiro A, Busch-Nentwich E et al (2008) Organ-specific requirements for Hdac1 in liver and pancreas formation. Dev Biol 322:237–250

    Google Scholar 

  • Park SW, Davison JM, Rhee J et al (2008) Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas. Gastroenterology 134:2080–2090

    Article  PubMed  Google Scholar 

  • Parkin DM, Whelan SL, Ferlay J et al (2002) Cancer incidence in five continents, vol VIII. International Agency for Research on Cancer, Lyon, France

    Google Scholar 

  • Patton EE, Widlund HR, Kutok JL et al (2005) BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol 15:249–254

    Article  CAS  PubMed  Google Scholar 

  • Ryu B, Jones J, Blades NJ et al (2002) Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res 62:819–826

    CAS  PubMed  Google Scholar 

  • Schauerte HE, van Eeden FJ, Fricke C et al (1998) Sonic hedgehog is not required for the induction of medial floor plate cells in the zebrafish. Development 125:2983–2993

    CAS  PubMed  Google Scholar 

  • Shen J, Person MD, Zhu J et al (2004) Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res 64:9018–9026

    Article  CAS  PubMed  Google Scholar 

  • Spitsbergen J (2007) Imaging neoplasia in zebrafish. Nat Methods 4:548–549

    Article  CAS  PubMed  Google Scholar 

  • Stemple DL (2004) Tilling- a high- throughput harvest for functional genomics. Nat Rev Genet 5:1–6

    Article  Google Scholar 

  • Stern HM, Murphey RD, Shepard JL et al (2005) Small molecules that delay S phase suppress a zebrafish bmyb mutant. Nat Chem Biol 1:366–370

    Article  CAS  PubMed  Google Scholar 

  • Stoletov K, Montel V, Lester RD et al (2007) High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish. Proc Natl Acad Sci USA 104:17406–17411

    Article  CAS  PubMed  Google Scholar 

  • Streisinger G, Walker C, Dower N et al (1981) Production of clones of homozygous diploid zebra fish (Brachydanio rerio). Nature 291:293–296

    Article  CAS  PubMed  Google Scholar 

  • Stuckenholz C, Lu L, Thakur P et al (2009) FACs-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development. Gastroenterology 137:1321–1332

    Google Scholar 

  • Szafranska AE, Davison TS, John J et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442–4452

    Google Scholar 

  • Tay TL, Lin Q, Seow TK et al (2006) Proteomic analysis of protein profiles during early development of the zerbafish, Danio rerio. Proteomics 6:3176–3188

    Article  CAS  PubMed  Google Scholar 

  • Thayer SP, Magliano MP, Heiser PW et al (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856

    Article  CAS  PubMed  Google Scholar 

  • Tiso N, Moro E, Argenton F (2009) Zebrafish pancreas development. Mol Cell Endocrinol 312:24–30

    Google Scholar 

  • Topczewska K, Postovit LM, Margaryan NV et al (2006) Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med 12: 925–932

    Article  CAS  PubMed  Google Scholar 

  • Varga ZM, Amores A, Lewis KE et al (2001) Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128:3497–3509

    CAS  PubMed  Google Scholar 

  • Wan H, Korzh S, Li Z et al (2006) Analyses of pancreas development by generation of gfp transgenic zebrafish using an exocrine pancreas-specific elastaseA gene promoter. Exp Cell Res 312:1526–1539

    Article  CAS  PubMed  Google Scholar 

  • White RJ (2008) RNA polymerases I and III, non-coding RNAs and cancer. Trends Genet 24:622–629

    Article  CAS  PubMed  Google Scholar 

  • White RM, Sessa A, Burke C et al (2008) Transparent adult zebrafish as tool for in vivo transplantation analysis. Cell Stem Cell 2:183–189

    Article  CAS  PubMed  Google Scholar 

  • Yee NS, Pack M (2005) Zebrafish as a model for pancreatic cancer research. Methods Mol Med 103:273–298

    CAS  PubMed  Google Scholar 

  • Yee NS, Yusuff S, Pack M (2001) Zebrafish pdx1 morphant displays defects in pancreas development and digestive organ chirality, and potential identifies a multipotent pancreas progenitor cell. Genesis 30:137–140

    Article  CAS  PubMed  Google Scholar 

  • Yee NS, Furth EE, Pack M (2003) Clinicopathologic and molecular features of pancreatic adenocarcinoma associated with Peutz-Jeghers Syndrome. Cancer Biol Ther 2:1 38–47

    Google Scholar 

  • Yee NS, Lorent K, Pack M (2005) Exocrine pancreas development in zebrafish. Dev Biol 284:84–101

    Article  CAS  PubMed  Google Scholar 

  • Yee NS, Gong W, Huang Y et al (2007) Mutation of RNA pol III subunit rpc2/polr3b leads to deficiency of subunit Rpc11 and disrupts zebrafish digestive development. PLoS Biol 5:2484–2492

    Article  CAS  Google Scholar 

  • Yee NS, Zhou W, Chun SG, Liang I-C (submitted) Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

    Google Scholar 

  • Zecchin E, Mavropoulos A, Devos N et al (2004) Evolutionary conserved role of ptfla in the specification of exocrine pancreatic fates. Dev Biol 268:174–184

    Article  CAS  PubMed  Google Scholar 

  • Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nature Rev Drug Discov 4:35–44

    Article  CAS  Google Scholar 

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Acknowledgments

The work in the author’s laboratory is supported by the National Institutes of Health (DK060529, DK071960); Pilot Grant in Translational Research by the Department of Internal Medicine of the University of Iowa; the American Cancer Society Junior Faculty Seed Grant Award (ACS #IRG-77-004-31); the Fraternal Order of Eagles, and the Cancer Center Support Grant (CA086862) by the National Cancer Institute to the Holden Comprehensive Cancer Center at the University of Iowa. The Zebrafish International Resource Center is supported by a grant (RR12546) from the NIH-NCRR.

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Authors and Affiliations

  1. Carver College of Medicine, Holden Comprehensive Cancer Center, University of Iowa, 500 Newton Road, Iowa City, IA, 52242, USA

    Nelson S. Yee

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  1. Nelson S. Yee
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Correspondence to Nelson S. Yee .

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Editors and Affiliations

  1. Institute, Translational Genomics Research, 445 N. Fifth Street, Phoenix, 85004, U.S.A.

    Haiyong Han

  2. Feinberg School of Medicine, Northwestern University, Chicago, 60611, U.S.A.

    Paul Grippo

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Yee, N. (2010). Zebrafish as a Biological System for Identifying and Validating Therapeutic Targets and Compounds. In: Han, H., Grippo, P. (eds) Drug Discovery in Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1160-5_5

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