2. Academic Validation
  3. WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma

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

  • Oncogene. 2014 Feb 13;33(7):899-908. doi: 10.1038/onc.2013.23.
M D Arensman 1,  A N Kovochich 1,  R M Kulikauskas 2,  A R Lay 1,  P-T Yang 2,  X Li 3,  T Donahue 4,  M B Major 5,  R T Moon 2,  A J Chien 6,  D W Dawson 3
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 2 Howard Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
  • 3 1] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [2] Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 4 1] Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [2] 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.
  • 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.
  • 6 1] Howard Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA [2] Department of Medicine, Division of Dermatology, University of Washington School of Medicine, Seattle, WA, USA.
PMID: 23416978 DOI: 10.1038/onc.2013.23
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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