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, Kelvin K. Tsai

研究成果: Article

28 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)1110-1120
頁數11
期刊Gastroenterology
145
發行號5
DOIs
出版狀態Published - 2013 十一月

指紋

Morphogenesis
Transcriptome
Adenocarcinoma
Neoplasms
Gene Expression
Catenins
Neoplasm Grading
Pancreatic Ducts
Computational Biology
Tumor Cell Line
Basement Membrane
Genes
Molecular Biology
Carcinogenesis
Up-Regulation
Stem Cells
Epithelial Cells
Pathology

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

引用此文

Wang, W. Y., Hsu, C. C., Wang, T. Y., Li, C. R., Hou, Y. C., Chu, J. M., ... Tsai, K. K. (2013). A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression. Gastroenterology, 145(5), 1110-1120. https://doi.org/10.1053/j.gastro.2013.07.040
Wang, Wei Yu ; Hsu, Chung Chi ; Wang, Ting Yun ; Li, Chi Rong ; Hou, Ya Chin ; Chu, Jui Mei ; Lee, Chung Ta ; Liu, Ming Sheng ; Su, Jimmy J.M. ; Jian, Kuan Ying ; Huang, Shenq Shyang ; Jiang, Shih Sheng ; Shan, Yan Shen ; Lin, Pin Wen ; Shen, Yin Ying ; Lee, Michael T.L. ; Chan, Tze Sian ; Chang, Chun Chao ; Chen, Chung Hsing ; Chang, I. Shou ; Lee, Yen Ling ; Chen, Li Tzong ; Tsai, Kelvin K. / A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression. 於: Gastroenterology. 2013 ; 卷 145, 編號 5. 頁 1110-1120.
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title = "A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression",
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.",
author = "Wang, {Wei Yu} and Hsu, {Chung Chi} and Wang, {Ting Yun} and Li, {Chi Rong} and Hou, {Ya Chin} and Chu, {Jui Mei} and Lee, {Chung Ta} and Liu, {Ming Sheng} and Su, {Jimmy J.M.} and Jian, {Kuan Ying} and Huang, {Shenq Shyang} and Jiang, {Shih Sheng} and Shan, {Yan Shen} and Lin, {Pin Wen} and Shen, {Yin Ying} and Lee, {Michael T.L.} and Chan, {Tze Sian} and Chang, {Chun Chao} and Chen, {Chung Hsing} and Chang, {I. Shou} and Lee, {Yen Ling} and Chen, {Li Tzong} and Tsai, {Kelvin K.}",
year = "2013",
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journal = "Gastroenterology",
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Wang, WY, Hsu, CC, Wang, TY, Li, CR, Hou, YC, Chu, JM, Lee, CT, Liu, MS, Su, JJM, Jian, KY, Huang, SS, Jiang, SS, Shan, YS, Lin, PW, Shen, YY, Lee, MTL, Chan, TS, Chang, CC, Chen, CH, Chang, IS, Lee, YL, Chen, LT & Tsai, KK 2013, 'A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression', Gastroenterology, 卷 145, 編號 5, 頁 1110-1120. https://doi.org/10.1053/j.gastro.2013.07.040

A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression. / Wang, Wei Yu; Hsu, Chung Chi; Wang, Ting Yun; Li, Chi Rong; Hou, Ya Chin; Chu, Jui Mei; Lee, Chung Ta; Liu, Ming Sheng; Su, Jimmy J.M.; Jian, Kuan Ying; Huang, Shenq Shyang; Jiang, Shih Sheng; Shan, Yan Shen; Lin, Pin Wen; Shen, Yin Ying; Lee, Michael T.L.; Chan, Tze Sian; Chang, Chun Chao; Chen, Chung Hsing; Chang, I. Shou; Lee, Yen Ling; Chen, Li Tzong; Tsai, Kelvin K.

於: Gastroenterology, 卷 145, 編號 5, 11.2013, p. 1110-1120.

研究成果: Article

TY - JOUR

T1 - A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression

AU - Wang, Wei Yu

AU - Hsu, Chung Chi

AU - Wang, Ting Yun

AU - Li, Chi Rong

AU - Hou, Ya Chin

AU - Chu, Jui Mei

AU - Lee, Chung Ta

AU - Liu, Ming Sheng

AU - Su, Jimmy J.M.

AU - Jian, Kuan Ying

AU - Huang, Shenq Shyang

AU - Jiang, Shih Sheng

AU - Shan, Yan Shen

AU - Lin, Pin Wen

AU - Shen, Yin Ying

AU - Lee, Michael T.L.

AU - Chan, Tze Sian

AU - Chang, Chun Chao

AU - Chen, Chung Hsing

AU - Chang, I. Shou

AU - Lee, Yen Ling

AU - Chen, Li Tzong

AU - Tsai, Kelvin K.

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

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U2 - 10.1053/j.gastro.2013.07.040

DO - 10.1053/j.gastro.2013.07.040

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