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WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma

Oncogene volume 33, pages 899–908 (2014)Cite this article

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Abstract

Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression-based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation. An experimentally generated, pancreas-specific gene expression signature of Wnt/β-catenin transcriptional activation was used to stratify pathway activation across a cohort of resected, early-stage PDAC tumors (N=41). In this cohort, higher Wnt/β-catenin activation was found to significantly correlate with lymphvascular invasion and worse disease-specific survival (median survival time 20.3 versus 43.9 months, log-rank P=0.03). Supporting the importance of Wnt ligand in mediating autocrine Wnt signaling, Wnt/β-catenin activity was significantly inhibited in PDAC cell lines by WLS gene silencing and the small-molecule inhibitor IWP-2, both of which functionally block Wnt ligand processing and secretion. Transcriptional profiling revealed elevated expression of WNT7B occurred in PDAC cell lines with high levels of cell autonomous Wnt/β-catenin activity. Gene-knockdown studies in AsPC-1 and HPAF-2 cell lines confirmed WNT7B-mediated cell autonomous Wnt/β-catenin activation, as well as an anchorage-independent growth phenotype. Our findings indicate WNT7B can serve as a primary determinant of differential Wnt/β-catenin activation in PDAC. Disrupting the interaction between Wnt ligands and their receptors may be a particularly suitable approach for therapeutic modulation of Wnt/β-catenin signaling in PDAC and other cancer contexts where Wnt activation is mediated by ligand expression rather than mutations in canonical pathway members.

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References

  1. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M . Pancreatic cancer. Lancet 2011; 378: 607–620.

    PubMed  PubMed Central  Google Scholar 

  2. Hong SM, Park JY, Hruban RH, Goggins M . Molecular signatures of pancreatic cancer. Arch Pathol Lab Med 2011; 135: 716–727.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Maitra A, Hruban RH . Pancreatic cancer. Annu Rev Pathol 2008; 3: 157–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. American_Cancer_Society, Cancer Facts & Figures 2012. Cancer. American Cancer Society, New York, 2012, pp 1–66.

  5. Donahue T, Tran L, Hill R, Li Y, Kovochich A, Calvopina J et al. Intergrative survival-based molecular profiling of human pancreatic cancer. Clin Cancer Res 2012; 18: 1352–1363.

    Article  CAS  PubMed  Google Scholar 

  6. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–1806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M . Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res 2011; 17: 4341–4354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Clevers H, Nusse R . Wnt/beta-catenin signaling and disease. Cell 2012; 149: 1192–1205.

    Article  CAS  PubMed  Google Scholar 

  9. Angers S, Moon RT . Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 2009; 10: 468–477.

    Article  CAS  PubMed  Google Scholar 

  10. Chien AJ, Conrad WH, Moon RTA . Wnt survival guide: from flies to human disease. J Invest Dermatol 2009; 129: 1614–1627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lucero OM, Dawson DW, Moon RT, Chien AJ . A re-evaluation of the ‘oncogenic’ nature of Wnt/beta-catenin signaling in melanoma and other cancers. Curr Oncol Rep 2010; 12: 314–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Caca K, Kolligs FT, Ji X, Hayes M, Qian J, Yahanda A et al. Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differ 1999; 10: 369–376.

    CAS  PubMed  Google Scholar 

  13. Gerdes B, Ramaswamy A, Simon B, Pietsch T, Bastian D, Kersting M et al. Analysis of beta-catenin gene mutations in pancreatic tumors. Digestion 1999; 60: 544–548.

    Article  CAS  PubMed  Google Scholar 

  14. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491: 399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One 2007; 2: e1155.

    Article  PubMed  PubMed Central  Google Scholar 

  16. White BD, Chien AJ, Dawson DW . Dysregulation of Wnt/beta-catenin signaling in gastrointestinal cancers. Gastroenterology 2012; 142: 219–232.

    Article  CAS  PubMed  Google Scholar 

  17. Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006; 8: 279–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD . Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2007; 2: e392.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell 2009; 15: 207–219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhong Y, Wang Z, Fu B, Pan F, Yachida S, Dhara M et al. GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS One 2011; 6: e22129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morris JPt, Wang SC, Hebrok M . KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 2010; 10: 683–695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Biechele TL, Moon RT . Assaying beta-catenin/TCF transcription with beta-catenin/TCF transcription-based reporter constructs. Methods Mol Biol 2008; 468: 99–110.

    Article  CAS  PubMed  Google Scholar 

  23. Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F . Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 2002; 22: 1172–1183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang JT, Gatza ML, Lucas JE, Barry WT, Vaughn P, Nevins JR . SIGNATURE: a workbench for gene expression signature analysis. BMC Bioinformatics 2011; 12: 443.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 2009; 5: 100–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009; 461: 614–620.

    Article  CAS  PubMed  Google Scholar 

  27. Port F, Basler K . Wnt trafficking: new insights into Wnt maturation, secretion and spreading. Traffic 2010; 11: 1265–1271.

    Article  CAS  PubMed  Google Scholar 

  28. Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 2012; 487: 510–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lowe AW, Olsen M, Hao Y, Lee SP, Taek Lee K, Chen X et al. Gene expression patterns in pancreatic tumors, cells and tissues. PLoS One 2007; 2: e323.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Heiser PW, Cano DA, Landsman L, Kim GE, Kench JG, Klimstra DS et al. Stabilization of beta-catenin induces pancreas tumor formation. Gastroenterology 2008; 135: 1288–1300.

    Article  CAS  PubMed  Google Scholar 

  31. Morris JPt, Cano DA, Sekine S, Wang SC, Hebrok M . Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest 2010; 120: 508–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Froeling FE, Feig C, Chelala C, Dobson R, Mein CE, Tuveson DA et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 2011; 141: 1486–1497.

    Article  CAS  PubMed  Google Scholar 

  33. Froeling FE, Mirza TA, Feakins RM, Seedhar A, Elia G, Hart IR et al. Organotypic culture model of pancreatic cancer demonstrates that stromal cells modulate E-cadherin, beta-catenin, and Ezrin expression in tumor cells. Am J Pathol 2009; 175: 636–648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chien AJ, Moon RT . WNTS and WNT receptors as therapeutic tools and targets in human disease processes. Front Biosci 2007; 12: 448–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA 2012; 109: 11717–11722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kovochich AN, Arensman MD, Lay AR, Rao NP, Donahue T, Li X et al. HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma. Cancer 2013; 119: 529–539.

    Article  Google Scholar 

  37. Liu N, Furukawa T, Kobari M, Tsao MS . Comparative phenotypic studies of duct epithelial cell lines derived from normal human pancreas and pancreatic carcinoma. Am J Pathol 1998; 153: 263–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li C, Wong WH . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 2001; 98: 31–36.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

DWD was supported by an American Cancer Society Research Scholar Grant, an American Association for Cancer Research/Pancreatic Cancer Action Network Career Development Award in memory of Seena Magowitz and a Research Services Research Fund Grant from the UCLA Department of Pathology. AJC was supported by a Career Development Award (1K08128565) from the NCI/NIH and Bridge Funding from the University of Washington Office of the Provost. MDA was supported by the UCLA Tumor Biology Program (USHHS Ruth L. Kirschstein Institutional National Research Service Award # T32 CA009056).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    M D Arensman, A N Kovochich, A R Lay, X Li & D W Dawson

  2. Department of Pharmacology, Howard Hughes Medical Institute, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA

    R M Kulikauskas, P-T Yang, R T Moon & A J Chien

  3. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    X Li, T Donahue & D W Dawson

  4. Department of Surgery, Division of General Surgery, Institute for Molecular Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    T Donahue

  5. Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    M B Major

  6. Department of Medicine, Division of Dermatology, University of Washington School of Medicine, Seattle, WA, USA

    A J Chien

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  1. M D Arensman
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Correspondence to A J Chien or D W Dawson.

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Arensman, M., Kovochich, A., Kulikauskas, R. et al. WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma. Oncogene 33, 899–908 (2014). https://doi.org/10.1038/onc.2013.23

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