Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Pervasive subtypes of pancreatic ductal adenocarcinoma (PDA) and their differing response to therapy.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis and current treatments are only modestly effective. We present evidence that this variation is caused in part by recurrent, pervasive molecular differences between tumors. mRNA expression profiles measured using microdissected PDA clinical samples reveal three dominant subtypes of disease; epithelial, mesenchymal and acinar-like. The classical and quasi-mesenchymal subtypes are observed in human and mouse PDA cell lines. Importantly, responses to cytotoxics and KRAS depletion in human PDA cell lines differ substantially between subtypes, and in opposing directions. Integrated genomics implicate and functional studies support overexpression of the trancription factor GATA6 as a driver of the epithelial subtype. These results provide a molecular framework for evaluating the prospects of personalized treatment in PDA. RNA was extracted from archival patient FFPE PDA samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from human PDA cell line samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from mouse PDA cell lines and hybridized on Affymetrix Mouse 430a 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA.

ORGANISM(S): Mus musculus

SUBMITTER: Anguraj Sadanandam

PROVIDER: E-GEOD-17891 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.

Collisson Eric A EA Sadanandam Anguraj A Olson Peter P Gibb William J WJ Truitt Morgan M Gu Shenda S Cooc Janine J Weinkle Jennifer J Kim Grace E GE Jakkula Lakshmi L Feiler Heidi S HS Ko Andrew H AH Olshen Adam B AB Danenberg Kathleen L KL Tempero Margaret A MA Spellman Paul T PT Hanahan Douglas D Gray Joe W JW

Nature medicine 20110403 4

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in whi ...[more]

PMID: 21460848

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Project description:Neural stem cells (NSCs) are considered to be the cell-of-origin of brain tumor stem cells. To identify the genetic pathways responsible for the transformation of normal NSCs to brain-tumor-initiating cells, we used Sleeping Beauty (SB) transposons, to mutagenize NSCs. Mobilized SB transposons induced the immortalization of NSCs. Immortalized NSCs induced tumors upon subcutaneous transplantation in immunocompromized mice. To further classify the immortalized cells and mouse tumors, we performed Gene Set Enrichment Analysis (GSEA) using DNA microarray data. Ten immortalized NSC lines (four WT and six p53 mutant lines) and two normal NSCs were used for RNA extraction and hybridization on Affymetrix microarrays. CEL files were processed using the RMA algorithm to normalize the data. Unsupervised hierarchical clustering was applied to the normalized gene expression data across samples using the R module pvclust (Suzuki and Shimodaira, Bioinformatics 22, 1540-1542, 2006). Hierarchical clustering showed a close similarity in gene expression between all ten immortalized lines, compared with two normal NSCs. We then compared their gene expression profiles to those present in the brain transcriptome database (Cahoy et al., J Neurosci 28, 264-278, 2008). Using five gene sets that are associated with neurons, oligodendrocytes, OPCs, astrocytes and cultured astroglial cells, GSEA enrichment scores were calculated for the ten immortalized NSCs lines against two control normal NSCs. GSEA enrichment analysis was performed using GSEA software v. 2.07 (http://www.broadinstitute.org/gsea). We found a strong enrichment for genes that are differentially expressed in the cultured astroglial cells. Twelve tumors (six WT and six p53 mutant tumors) and three control subcutaneous tissues were used for RNA extraction and hybridization on Affymetrix microarrays. CEL files were processed using the RMA algorithm to normalize the data. Unsupervised hierarchical clustering was applied to the normalized gene expression data across samples using the R module pvclust (Suzuki and Shimodaira, Bioinformatics 22, 1540-1542, 2006). Hierarchical clustering of 12 tumors showed a close similarity between the tumors, compared with three control subcutaneous tissues. We next performed GSEA analysis on the tumors. Using gene sets specific to the four defined GBM subtypes (Verhaak et al., Cancer Cell 17, 98-110, 2010), a GSEA enrichment score was then calculated for the twelve tumor samples against three control subcutaneous tissue samples. GSEA enrichment analysis was performed using GSEA software v. 2.07 (http://www.broadinstitute.org/gsea). This analysis showed that the mouse tumors were significantly enriched for genes specific for the mesenchymal GBM.

Dataset Information

Pervasive subtypes of pancreatic ductal adenocarcinoma (PDA) and their differing response to therapy.

Publications

Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.

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