Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression Data from 24 orthotopic tumors grown in the pancreas of mice +/- MEK inhibitor PD0325901

ABSTRACT: Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. We used microarrays to find gene expression patterns associated with drug response and also identified genes regulated by the MAP kinase pathway 6 pancreatic cell lines were injected into the pancreas of nude mice and treated either with vehicle control or PD0325901 for 12 plus 12 hours.

ORGANISM(S): Homo sapiens

SUBMITTER: Stephan Gysin

PROVIDER: E-GEOD-45758 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity.

Gysin Stephan S Paquette Jesse J McMahon Martin M

Molecular cancer research : MCR 20120725 12

Mutationally activated KRAS, detected in approximately 90% of pancreatic ductal adenocarcinomas (PDA), has proven an intractable pharmacologic target to date. Consequently, efforts to treat KRAS-mutated cancers are focused on targeting RAS-regulated signaling pathways. In mouse models, expression of BRAF(V600E) combined with dominant-negative TP53 elicits PDA, and pharmacologic blockade of mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibits proliferation of human PDA-d ...[more]

PMID: 22833572

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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.

Project description:The VEGF targeted antiangiogenic drug bevacizumab has shown varying results in clinical trials of breast cancer. Identifying robust biomarkers for selecting patients that may benefit from bevacizumab treatment and for monitoring of response is important for the future use of this drug. Two established xenograft models representing basal-like and luminal-like breast cancer were used to study bevacizumab treatment response on the metabolic and gene expression levels. Mice given no treatment or treated with bevacizumab, doxorubicin or the combination of these two drugs were sacrificed at day 3 or 10. High resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and gene expression microarray analysis was performed on all tumor samples. Combination treatment with bevacizumab had the strongest growth inhibiting effect in the basal-like tumors, and this was reflected in a significant response in the metabolomic and transcriptomic profiles. In the luminal-like xenografts, addition of bevacizumab did not improve the effect of doxorubicin. On the global transcriptomic level, the largest changes in gene expression were observed for the most efficient treatment in each of the two xenograft models. The metabolite glycerophosphocholine (GPC) showed opposite response in the treated xenografts compared with untreated controls: lower in basal-like tumors and higher in luminal-like tumors. Lower levels of creatine, taurine and glycine were observed in the basal-like xenografts given bevacizumab as monotherapy compared with untreated xenografts. Comparing combination therapy with doxorubicin monotherapy in basal-like xenografts, 14 genes showed significant differential expression, including higher expression of very low density lipoprotein receptor (VLDLR), and lower expression of hemoglobin, theta 1 (HBQ1). Using published gene expression signatures, bevacizumab treated tumors were associated with a more hypoxic phenotype, while no evidence was found for associations between bevacizumab treatment and vascular invasion or increasing tumor grade. This study underlines the importance of characterizing biological differences between subtypes of breast cancer to identify personalized biomarkers for selecting patients for bevacizumab treatment and evaluating response to therapy. 60 samples are analyzed. For each of the two xenograft models, tumors were collected from animals that were untreated or treated with bevacizumab (5 mg/kg), doxorubicin (8 mg/kg) or a combination of the two therapies (n = 6 tumors for each group). Bevacizumab treatment was repeated at day 4 and day 7. Animals were sacrificed and tissue harvested at either day 3 or 10 after treatment, in triplicates within each treatment group. This resulted in 24 tumor samples from each of the models. In addition, untreated and bevacizumab treated luminal-like xenografts not fed with estradiol were included for comparison (n = 12). Note that the untreated controls are overlapping with the samples in the GEO series with accession number: GSE25915.

Dataset Information

Expression Data from 24 orthotopic tumors grown in the pancreas of mice +/- MEK inhibitor PD0325901

Publications

Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity.

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