Comprehensive transcriptome analysis in Babao Dan treated pancreatic cancer cell line derived xenograft mouse models
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138963 | GEO | 2020/12/09
REPOSITORIES: GEO
Similar Datasets
Project description:We generated novel patient derived xenograft (PDX) and cell line -derived xenograft models for pancreatic ductal adenocarcinoma (PDAC) which reflect different molecular subtypes. Pancreatic ductal adenocarcinoma is currently the tumor with the fourth highest mortality rate. Recently, subtypes of PDAC have been reported by Collisson et al (Nat. Med. 17(4) 2011. DOI: 10.1038/nm.2344). However current fetal calf serum (FCS) cultured cell lines do not accurately model these subtypes. We thus generated novel serum-free cell lines derived from primary patient xenografts. We here analyse the gene-expression profiles of the xenografts and the derived cell lines. We show that indeed three different subtypes can be separated in our models based on gene-expression data. Further, we identify upregulation of a drug-detoxification pathway specifically in xenografts and cell lines of one of the subtypes. These models and data will help to better understand inter-patient heterogeneity in PDAC and identify novel drug targets and diagnostic markers.
2016-01-12 | E-MTAB-4029 | biostudies-arrayexpress
Project description:Comprehensive transcriptome analysis in Babao Dan treated pancreatic cancer cell line derived xenograft mouse models
| PRJNA577900 | ENA
Project description:Pancreatic adenocarcinoma (PDAC) is one of the most lethal human malignancies and a major health problem. Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. We generated subcutaneous PDX from PDAC samples obtained either surgically or using diagnostic biopsies (endoscopic ultrasound guided fine needle aspirate). The extensive multiomics characterization of the xenografts demonstrated that PDX is a suitable model for preclinical studies, representing the diversity of the primary cancers. this dataset, describe the RNA sequencing data used in the multiomics study.
2017-12-12 | E-MTAB-5039 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003
2012-05-02 | E-GEOD-37645 | biostudies-arrayexpress
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.
2013-10-01 | E-GEOD-46385 | biostudies-arrayexpress
Project description:The aim of this study is to compare the transcriptomic profiles of various ex vivo models of pancreatic cancer. First, primary tumours and their corresponding xenografts in nude mice were analysed by RNA-seq. Monocultures of pancreatic cancer cells derived from the xenografts were then prepared as 2D monolayers, Matrigel-embedded organoids, spheres in suspension and 3D cultures in self-assembling peptide amphiphile (PA) hydrogels. Seven-day cultures were then analysed by RNA-seq. The results suggest that all ex vivo monocultures retain patient-specific transcriptional profiles, especially cancer stem cell signatures, while being deficient in the expression of stromal components such as the core matrisome. Correlations with the primary tumours were generally higher in PA hydrogels than organoids. Biased gene expression signatures were identified in certain models. This is the first study to explore the transcriptomic signatures of four different ex vivo models matched to their primary tumours of origin.
2021-07-03 | GSE139184 | GEO
Project description:Pancreatic ductal adenocarcinoma has a very poor prognosis, and new therapies and preclinical models are urgently needed. We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), and integrated these to create 13 matched trios, as systematic models for this cancer. Orthotopic implantation (OI) of PDCLs showed tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDX and OI-PDX with passaged tumors showed that histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. Comparing gene expression in PDCLs, ectopic tumors, and OI tumors, CXCR4 and CXCL12 genes were specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. These patient-derived tumor models provide useful tools for preclinical research into pancreatic ductal adenocarcinoma. We performed comprehensive gene expression profiling of 13 pancreatic cancer cell lines, 14 CDX and 14 PDX tumors by Affymetrix Gene Chip HG-U133Plus2.0.
2022-02-16 | GSE157494 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of relatively few tumor cells surrounded a heterocellular non-cancerous cell population embedded in extracellular matrix, collectively named stroma. Despite the recognition that the stroma is an important contributor to the typically poor outcome of PDAC, its analysis has been hampered by the analysis of bulk tissue. Here we present a landscape of human epithelial PDAC cells of primary tumors (n=6) and metastases (n=4) in a mouse stroma background.
2021-09-09 | PXD017393 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE25273: Array Comparative Genomic Hybridization of Pancreatic Xenografts and Cell Lines GSE26088: Expression Profiling of Pancreatic Xenografts and Cell Lines Refer to individual Series
2011-12-15 | E-GEOD-26089 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC.
2012-05-03 | GSE37645 | GEO