A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression

Wei Yu Wang, Chung Chi Hsu, Ting Yun Wang, Chi Rong Li, Ya Chin Hou, Jui Mei Chu, Chung Ta Lee, Ming Sheng Liu, Jimmy J M Su, Kuan Ying Jian, Shenq Shyang Huang, Shih Sheng Jiang, Yan Shen Shan, Pin Wen Lin, Yin Ying Shen, Michael T L Lee, Tze Sian Chan, Chun Chao Chang, Chung Hsing Chen, I. Shou ChangYen Ling Lee, Li Tzong Chen, Kun-Chih Tsai

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Background & Aims Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases after surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. Methods We generated architectures of human pancreatic duct epithelial cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. Results We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well after surgery. Based on this profile, we established a 6-28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%-95.0%). One gene, ASPM, was down-regulated during tubulogenesis but up-regulated in human PDAC cell lines and tumor samples; up-regulation correlated with patient outcomes (Cox regression P =.0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-β-catenin signaling and stem cell features of PDAC cells. Conclusions We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture-specific signature of PDAC cells that is associated with patient outcomes after surgery.

Original languageEnglish
Pages (from-to)1110-1120
Number of pages11
JournalGastroenterology
Volume145
Issue number5
DOIs
Publication statusPublished - Nov 2013

Keywords

  • Biomarker
  • Pancreatic Cancer
  • Prognostic Factor
  • Tumor Progression

ASJC Scopus subject areas

  • Gastroenterology

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