Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Combinatorial analysis of miRNA and mRNA expression in pancreatic ductal adenocarcinoma (PDAC)_mRNA

ABSTRACT: miRNAs are known to be involved in PDAC tumorigenesis, but only a few biologically relevant gene targets have been identified. Here we show that three miRNAs (miR-21, miR-23a and miR-27a) act in concert for the cooperative suppression of several tumor suppressor genes of which we experimentally validated PDCD4, BTG2 and NEDD4L. The synergistic inhibition of this triple miRNA combination is capable of reducing PDAC growth in a mouse model greater than inhibition of oncomiR-21 alone. Patients samples of normal pancreas (n=6) or pancreatic ductal adenocarcinoma (PDAC; n=6) were retrieved during surgery and placed in RNA Later stabilization fluid and then kept at minus 80 until required.

ORGANISM(S): Homo sapiens

SUBMITTER: Teresa Colombo

PROVIDER: E-GEOD-41368 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression.

Frampton Adam E AE Castellano Leandro L Colombo Teresa T Giovannetti Elisa E Krell Jonathan J Jacob Jimmy J Pellegrino Loredana L Roca-Alonso Laura L Funel Niccola N Gall Tamara M H TM De Giorgio Alexander A Pinho Filipa G FG Fulci Valerio V Britton David J DJ Ahmad Raida R Habib Nagy A NA Coombes R Charles RC Harding Victoria V Knösel Thomas T Stebbing Justin J Jiao Long R LR

Gastroenterology 20131009 1

<h4>Background & aims</h4>There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes.<h4>Methods</h4>We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We ...[more]

PMID: 24120476

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Project description:This project describes the establishment and validation of a murine orthotopic xenograft model using fresh human tumor samples that recapitulates the critical components of human pancreatic adenocarcinoma. The authors discuss the proven and theoretical advantages of the model as well as future translational implications. Background: Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC. Methods: Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase (RTK) activation, and cytokine expression. Results: Fifteen human PDACs were propagated orthotopically in mice. Xenografts developed peritoneal and liver metastases. Time to growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, p53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines. Conclusions: Our orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy. 47 Samples in total were generated for normal pancreatic tissue in patients, pancreatic tumors in patients, pancreatic tumors propagated in a mouse xenograft model, and pancreatic cancer cell lines in vitro. Clustering analysis was performed to evaluate the differences between patient tumors, xenograft tumors, established cancer cell lines, and cell lines derived from xenografts.

Dataset Information

Combinatorial analysis of miRNA and mRNA expression in pancreatic ductal adenocarcinoma (PDAC)_mRNA

Publications

MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression.

Similar Datasets

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