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 Chang, Yen-Ling Lee, Li-Tzong Chen, Kelvin K Tsai
Gastroenterology 2013, 145 (5): 1110-20

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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"