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A Gene Expression Signature of Epithelial Tubulogenesis and a Role for ASPM in Pancreatic Tumor Progression
- Source :
- Gastroenterology. 145:1110-1120
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
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.
- Subjects :
- Pathology
medicine.medical_specialty
endocrine system diseases
Nerve Tissue Proteins
Mice, SCID
Biology
medicine.disease_cause
Epithelium
ASPM
Mice
Cell Movement
Mice, Inbred NOD
Cancer stem cell
Pancreatic tumor
Pancreatic cancer
Biomarkers, Tumor
medicine
Animals
Humans
beta Catenin
Retrospective Studies
Pancreatic duct
Hepatology
Pancreatic Ducts
Gastroenterology
Cell Differentiation
Prognosis
medicine.disease
digestive system diseases
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Wnt Proteins
Disease Models, Animal
medicine.anatomical_structure
Tumor progression
Disease Progression
Heterografts
Stem cell
Transcriptome
Carcinogenesis
Carcinoma, Pancreatic Ductal
Follow-Up Studies
Signal Transduction
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 145
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....efa70aa7b781afe2d260c68650b38e0a