A comprehensive PDX gastric cancer collection captures cancer cell intrinsic transcriptional MSI traits.
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PROVIDER: PRJNA527795 | ENA |
REPOSITORIES: ENA
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Project description:Gastric cancer (GC) is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvement, the clinical outcome for patients with advanced GC is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multi-level platform of GC models, comprising 100 Patient-derived xenografts (PDXs), primary cell lines and organoids. Samples were classified according to their histology, microsatellite stability (MS) and Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution and it includes all the GC histologic and molecular types identified by TCGA. PDX histopathological features were consistent with those of patients’ primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number variation of tyrosine kinases/KRAS genes and MSI status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell intrinsic MSI signature, which was efficiently exported to gastric cancer, allowing the identification -among MSS patients- of a subset of MSI-like tumors with common molecular assets and significant better prognosis. We generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel 'druggable' targets and define the best therapeutic strategies. Moreover, transcriptomic analysis of GC PDXs allowed the identification of a cancer cell intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.
2019-10-15 | GSE128459 | GEO
Project description:Inhibition of the nonsense mediated decay (NMD) mechanism in cells results in stabilization of transcripts carrying premature translation termination codons. A strategy referred to as gene indentification by NMD inhibition (GINI) has been proposed to identify genes carrying nonsense mutations (Noensie & Dietz, 2001). Genes containing frameshift mutations in colon cancer cell line have been identifying mutatnt genes using GINI, we have now further improved the strategy. In this approach, inhibition of NMD with emetine is complemented with inhibiting NMD by blocking the phosphorylation of the hUpf1 protein with caffeine. In addition, to enhance the GINI strategy, comparing mRNA level alterations produced by inhibiting transcription alone or inhbiiting transcription together with NMD following caffeine pretreatment were used for the efficient identification of false positives produced as a result of stress response to NMD inhibition. To demonstrate the improved efficiency of this approach, we analyzed colon cancer cell lines showing microstellite instability. Bi-allelic inactivating mutations were found in the FXR1, SEC1L1, NCOR1, BAT3, PHD14, ZNF294, C190ORF5 genes as well as genes coding for proteins with yet unknown functions. Experiment Overall Design: Using GINI2 as a method of identifying novel biallelic truncating mutations in MSI+ colon cancer cells, various treatment conditions were applied to cultured colon cancer cell lines LS180 (MSI+) and SW480 (MSI-) and gene expression profiling was measured using Affymetrix GeneChip U133 Plus 2 arrays.
2008-06-13 | E-GEOD-5486 | biostudies-arrayexpress
Project description:Expression profiling was used to identify genes differentially expressed in MSS (microsatellite stable) and MSI (microsatellite unstable) colon cancer cell lines. Data submitted in support of manuscript entitled Villin expression is frequently lost in poorly differentiated colon cancer, Diego Arango, Sheren Al-Obaidi, David S. Williams, Jose Dopeso, Rocco Mazzolini, Georgia Corner, Do-Sun Byun, Carmel Murone, Lars Tögel, Nikolajs Zeps, Lauri A. Aaltonen, Barry Iacopetta and John M. Mariadason, American Journal of Pathology, 2012. 5 microsatellite stable (MSS) and 5 microsatellite unstable (MSI) colon cancer cell lines profiled. Each cell line grown and arrayed in duplicate, and the duplicates averaged for each cell line before calculating means for MSS and MSI lines.
2012-02-07 | E-GEOD-35566 | biostudies-arrayexpress
Project description:MSI analysis using blood-derived MSI markers
| PRJEB53321 | ENA
Project description:The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy across a population, but also study crucial aspects of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. The pathways most significantly altered included Protein Kinase A signaling, GNRH signaling, and sphingosine-1-phosphate signaling. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer 6 pairs of Patient-Derived Xenografts (PDX) were ananlyzed using RNA-seq for a total of 12 samples. Each pair consists of a treated and untreated PDX of ovarian cancer. Treated Ovarian cancer PDXs were treated with 4 weeks of a combination of carboplatin and taxol. RNA was isolated and converted to cDNA. RNA-seq was conductred on the Illumina HiSeq 2000 with 50 bp paired end sequencing
2015-06-17 | E-GEOD-58586 | biostudies-arrayexpress
Project description:There is a strong need to develop patient-derived xenograft (PDX) tumor models for studying new treatment options for gastric cancer (GC). With low engraftment success, few collections of GC PDX have been reported and molecular basis of the model establishment remain largely unknown. Here we established n=27 PDX models from n=100 GC tumors and compared their characteristics to GC patient tumors based on the recent work done by ACRG and TCGA, to evaluate the representativeness and relevance of the collection for drug testing. We show that MSI, CIN and MSS/TP53- tumors were preferentially established as PDX, while MSS/EMT and EBV not and that PDX models retained histology and molecular subtypes of parental tumors. By using synapse database, we identified 48 druggable alterations that could be investigated with the collection. Counting alterations for these 48 genes in PDX compared to TCGA tumors revealed models frequently classified with heavily altered tumors but well preserved genomic alteration patterns specific of each GC subtype. The molecular analysis of n=8/27 tumors and corresponding PDX at passage P1, P2 and P3 revealed variations in somatic alteration content both at single nucleotide and chromosomal level in highly unstable MSI and CIN tumors, with changes occurring mainly at P1. In two cases, we show likely emergence of rare subclones carrying known oncogenic alterations in KRAS and PIK3CA. Significance. This study presents a resource of fully annotated GC PDX models for anticancer agent testing. We show that beside close resemblance of PDX with parental tumors, not all subtypes are established, and that the clonal selection plays a key role the establishment of certain tumors. This may have a bearing on translation of observations into the clinic and underline the need to frequently survey the molecular characteristics of the PDX models.
2020-07-15 | GSE115637 | GEO
Project description:Microsatellite instability (MSI), caused by defective mismatch repair, is observed in a subset of colorectal cancers (CRCs). We evaluated somatic mutations in microsatellite repeats of genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat. Expression profiling of 34 MSI colorectal cancers and 15 normal colonic mucosas was performed in 2002. Comparison of malignant and healthy tissue.
2011-03-01 | E-GEOD-24514 | biostudies-arrayexpress
Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.
2008-12-18 | GSE13911 | GEO