Filters
Technology
Platform
GSE21687
Mus musculus, Homo sapiens
275 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genomic technologies have unmasked molecularly distinct subgroups among tumors of the same histological type; but understanding the biologic basis of these subgroups has proved difficult since their defining alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher complex genomic data sets by matching the genetic alterations contained within these, with candidate cells of origin, to generate accurate disease models. Using an integrated genomic analysis we first identified subgroups of human ependymoma: a form of neural tumor that arises throughout the central nervous system (CNS). Validated alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. Matching the transcriptomes of human ependymoma subgroups to those of distinct types of mouse radial glia (RG)neural stem cells (NSCs) that we identified previously to be a candidate cell of origin of ependymoma - allowed us to select RG types most likely to represent cells of origin of disease subgroups. The transcriptome of human cerebral ependymomas that amplify EPHB2 and delete INK4A/ARF matched most closely that of embryonic cerebral Ink4a/Arf-/- RG: remarkably, activation of EphB2 signaling in this RG type, but not others, generated highly penetrant ependymomas that modeled accurately the histology and transcriptome of one human cerebral tumor subgroup (subgroup D). Further comparative genomic analysis revealed selective alterations in the copy number and expression of genes that regulate neural differentiation, particularly synaptogenesis, in both mouse and human subgroup D ependymomas; pinpointing this pathway as a previously unknown target of ependymoma tumorigenesis. Our data demonstrate the power of comparative genomics to sift complex genetic data sets to identify key molecular alterations in cancer subgroups.
Publication Title
Cross-species genomics matches driver mutations and cell compartments to model ependymoma.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
Publication Title
Subtypes of medulloblastoma have distinct developmental origins.
Sample Metadata Fields
Specimen part
View Samples- Arabidopsis thaliana
- 9 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
ALTERED MERISTEM PROGRAM1 (AMP1) is a member of the M28 family of carboxypeptidases with a pivotal role in cell fate maintenance in the embryo and shoot meristem. A defect in AMP1 function results in suspensor to embryo conversion and a hypertrophic shoot meristem forming ectopic stem cell pools. However, so far the role of AMP1 in shoot development could not be assigned to a specific molecular pathway nor is its biochemical function resolved. Double mutants in CYP78A5 and CYP78A7 develop a similar set of cell fate defects. To further assess whether this phenotypic overlap is also depicted in a congruency at the global gene expression level, we analyzed the transcriptomic responses of both genotypes
Publication Title
AMP1 and CYP78A5/7 act through a common pathway to govern cell fate maintenance in Arabidopsis thaliana.
Sample Metadata Fields
Age, Specimen part
View Samples- Arabidopsis thaliana
- 31 Downloadable Samples
- Arabidopsis Gene 1.1 ST Array (aragene11st)
Description
Brassinosteroids (BRs) are growth-promoting plant hormones that play a role in abiotic stress responses, but molecular modes that enable this activity remain largely unknown. Here we show that BRs participate in the regulation of freezing tolerance. BR signaling-defective mutants of Arabidopsis thaliana were hypersensitive to freezing before and after cold acclimation. The constitutive activation of BR signaling, in contrast, enhanced freezing resistance. Evidence is provided that the BR-controlled basic helixloophelix transcription factor CESTA (CES) can contribute to the constitutive expression of the C-REPEAT/DEHYDRATION-RESPONSIVE ELEMENT BINDING FACTOR (CBF) transcriptional regulators that control cold responsive (COR) gene expression. In addition, CBF-independent classes of BR-regulated COR genes are identified that are regulated in a BR- and CES-dependent manner during cold acclimation. A model is presented in which BRs govern different cold-responsive transcriptional cascades through the posttranslational modification of CES and redundantly acting factors. This contributes to the basal resistance against freezing stress, but also to the further improvement of this resistance through cold acclimation.
Publication Title
Brassinosteroids participate in the control of basal and acquired freezing tolerance of plants.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Arabidopsis thaliana
- 21 Downloadable Samples
Arabidopsis Gene 1.1 ST Array (aragene11st), Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The Small Molecule Hyperphyllin Enhances Leaf Formation Rate and Mimics Shoot Meristem Integrity Defects Associated with AMP1 Deficiency.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Arabidopsis thaliana
- 12 Downloadable Samples
- Arabidopsis Gene 1.1 ST Array (aragene11st)
Description
ALTERED MERISTEM PROGRAM1 (AMP1) is a member of the M28 family of carboxypeptidases with a pivotal role in plant development and stress adaptation. Its most prominent mutant defect is a unique hypertrophic shoot phenotype combining a strongly increased organ formation rate with enhanced meristem size and the formation of ectopic meristem poles. However, so far the role of AMP1 in shoot development could not be assigned to a specific molecular pathway nor is its biochemical function resolved. We used a chemical genetic approach to identify the drug hyperphyllin (HP), which specifically mimics the shoot defects of amp1, including plastochron reduction and enlargement and multiplication of the shoot meristem. To further assess whether hyperphyllin acts in an AMP1-dependent manner we compared the transcriptonal responses of hyperphyllin-treated wild-type and amp1 mutant seedlings.
Publication Title
The Small Molecule Hyperphyllin Enhances Leaf Formation Rate and Mimics Shoot Meristem Integrity Defects Associated with AMP1 Deficiency.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Arabidopsis thaliana
- 9 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
ALTERED MERISTEM PROGRAM1 (AMP1) is a member of the M28 family of carboxypeptidases with a pivotal role in plant development and stress adaptation. Its most prominent mutant defect is a unique hypertrophic shoot phenotype combining a strongly increased organ formation rate with enhanced meristem size and the formation of ectopic meristem poles. However, so far the role of AMP1 in shoot development could not be assigned to a specific molecular pathway nor is its biochemical function resolved. We used a chemical genetic approach to identify the drug hyperphyllin (HP), which specifically mimics the shoot defects of amp1, including plastochron reduction and enlargement and multiplication of the shoot meristem. To further assess whether hyperphyllin acts in an AMP1-dependent manner we compared the transcriptonal responses of hyperphyllin-treated wild-type Arabidopsis seedlings with those of untreated amp1 mutant seedlings.
Publication Title
The Small Molecule Hyperphyllin Enhances Leaf Formation Rate and Mimics Shoot Meristem Integrity Defects Associated with AMP1 Deficiency.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
MiR-221 overexpression leads to activation of apoptosis, growth arrest and reduced invasivness in PCa cells. Interaction of miR-221 with potential target genes was analyzed by a genome wide expression profiling.. Regulation of selected genes and proteins identified in the gene array analysis was confirmed by Real Time RT-PCR assay (IRF1, IRF2 SOCS3, STAT1), and Western Blotting. In total, 282 genes were upregulated and 64 downregulated based on a more than 2-fold difference to untransfected PC-3 cells. Regulated genes are involved in apoptosis, hemostasis, oxidative stress response, tumorigenesis and inflammation. We confirmed dysregulation of IRF-2 SOCS3, STAT1,IRF9. These results indicate that miR-221 overexpression might lead to activation of the JAK/STAT pathway and downregulation of miR-221 might contribute to tumorigenesis in PCa cells.
Publication Title
Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Hypoxia triggers aggressive cancer growth and contributes to chemotherapy resistance. Novel therapeutic strategies aim at targeting hypoxia activated signaling pathways. Tumor hypoxia not only affects neoplastic tumor cells but also the surrounding stroma cells. Therefore, a novel ex vivo model was established, which allows the study of hypoxia effects in fragments of non-small cell lung cancer (NSCLC) with preserved tumor microenvironment and 3D-structure. Microarray analysis identified 107 significantly regulated genes with at least two-fold expression change in hypoxic compared to normoxic fragments. However, only four genes were significantly regulated in both subtypes, adenocarcinoma and squamous cell carcinoma. The hypoxic regulation of these four genes was verified in an independent set using quantitative PCR.
Publication Title
Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model - role of tumor stroma cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 9 Downloadable Samples
Illumina HiSeq 2000
Description
KRAS mutations are the ost abundand driver mutations found in lung adenocarcinoma patients. Unfortunately, there are no clinical approved inhibitors available, to directly target mutant forms of KRAS. The aim of the study was to unravel the impact of upstream Egfr activation in signaling of mutated K-ras. We found that upregulation of G12D mutant Kras induced genes was significantly impaired when Egfr was knocked out. Our data suggests that signaling of mutant Kras depends on upstream activation. This finding may be exploited therapeutically by targeting EGFR in KRAS mutant patients. Overall design: We isolated mouse alveolar type II cells and induced the Kras G12D mutation, with and without concomitant Egfr knockout, in vitro. Cells lysates were analyzed 5 days following transgene induction.
Publication Title
JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples