1. WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma
- Author
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Xin-Min Li, Michael D. Arensman, Anna R. Lay, Pei-Tzu Yang, Rima M. Kulikauskas, Randall T. Moon, Michael B. Major, Timothy R. Donahue, Anne N. Kovochich, Andy J. Chien, and David W. Dawson
- Subjects
Male ,Cancer Research ,Transcription, Genetic ,WNT7B ,pancreatic cancer ,Kaplan-Meier Estimate ,medicine.disease_cause ,2.1 Biological and endogenous factors ,Aetiology ,Wnt Signaling Pathway ,Cancer ,Tumor ,Wnt signaling pathway ,Wnt/beta-catenin signaling ,LRP6 ,LRP5 ,Middle Aged ,Prognosis ,Autocrine Communication ,Pancreatic Ductal ,Female ,Transcription ,Carcinoma, Pancreatic Ductal ,medicine.medical_specialty ,Cell signaling ,Clinical Sciences ,Oncology and Carcinogenesis ,Biology ,Article ,Cell Line ,Rare Diseases ,Genetic ,Internal medicine ,Cell Line, Tumor ,medicine ,Cell Adhesion ,Genetics ,Gene silencing ,Humans ,Oncology & Carcinogenesis ,Autocrine signalling ,Molecular Biology ,Proportional Hazards Models ,Cell Proliferation ,Aged ,Cell growth ,Carcinoma ,Pancreatic Neoplasms ,Wnt Proteins ,Endocrinology ,Cancer research ,Carcinogenesis ,Transcriptome ,Digestive Diseases ,Wnt/β-catenin signaling - 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.
- Published
- 2014