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GSE39397
Homo sapiens
49 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2), Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment, Subject
View Samples- Homo sapiens
- 23 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The survival of isolated metastatic cells and expansion into macroscopic tumour has been recognized as a limiting step for metastasis formation in several cancer types yet the determinants of this process remain largely uncharacterized. In colorectal cancer (CRC), we identify a transcriptional programme in tumour-associated stromal cells, which is intimately linked to a high risk of developing recurrent disease after therapy. A large proportion of CRCs display mutational inactivation of the TGF-beta pathway but paradoxically they are characterized by high TGF-beta production. In these tumours, TGF-beta instructs a transcriptional programme in stromal cells, which confers a high risk of developing metastatic disease.
Publication Title
Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm), Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The survival of isolated metastatic cells and expansion into macroscopic tumour has been recognized as a limiting step for metastasis formation in several cancer types yet the determinants of this process remain largely uncharacterized. In colorectal cancer (CRC), we identify a transcriptional programme in tumour-associated stromal cells, which is intimately linked to a high risk of developing recurrent disease after therapy. A large proportion of CRCs display mutational inactivation of the TGF-beta pathway but paradoxically they are characterized by high TGF-beta production. In these tumours, TGF-beta instructs a transcriptional programme in stromal cells, which confers a high risk of developing metastatic disease.
Publication Title
Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
Sample Metadata Fields
Disease, Disease stage, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The survival of isolated metastatic cells and expansion into macroscopic tumour has been recognized as a limiting step for metastasis formation in several cancer types yet the determinants of this process remain largely uncharacterized. In colorectal cancer (CRC), we identify a transcriptional programme in tumour-associated stromal cells, which is intimately linked to a high risk of developing recurrent disease after therapy. A large proportion of CRCs display mutational inactivation of the TGF-beta pathway but paradoxically they are characterized by high TGF-beta production. In these tumours, TGF-beta instructs a transcriptional programme in stromal cells, which confers a high risk of developing metastatic disease.
Publication Title
Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
ChIP-on-chip has emerged as a powerful tool to dissect the complex network of regulatory interactions between transcription factors and their targets. However, most ChIP-on-chip analysis methods use conservative approaches aimed to minimize false-positive transcription factor targets. We present a model with improved sensitivity in detecting binding events from ChIP-on-chip data. Its application to human T-cells, followed by extensive biochemical validation, reveals that three transcription factor oncogenes, NOTCH1, MYC, and HES1, bind to several thousands target gene promoters, up to an order of magnitude increase over conventional analysis methods. Gene expression profiling upon NOTCH1 inhibition shows broad-scale functional regulation across the entire range of predicted target genes, establishing a closer link between occupancy and regulation. Finally, the increased sensitivity reveals a combinatorial regulatory program in which MYC co-binds to virtually all NOTCH1-bound promoters. Overall, these results suggest an unappreciated complexity of transcriptional regulatory networks and highlight the fundamental importance of genome-scale analysis to represent transcriptional programs.
Publication Title
ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The neural transcription factor SOX11 is overexpressed in aggressive lymphoid neoplasms mainly in mantle cell lymphoma (MCL). We have recently demonstrated SOX11 tumorigenic potential in vivo by showing a significant reduction on tumor growth of SOX11-knockdown MCL cells in xenograft experiments, confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL (Vegliante et al., 2013). However, the specific mechanisms regulated by SOX11 that promote the oncogenic and rapid tumor growth of aggressive MCL still remain to be elucidated. To further characterize the potential oncogenic mechanisms regulated by SOX11 in MCL, we have analyzed the GEP derived from the xenograft SOX11-positive and knockdown xenograft derived tumors.
Publication Title
SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 21 Downloadable Samples
Illumina HiSeq 2000
Description
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid tumor derived from malignant transformation of T follicular helper (Tfh) cells. Genetically, AITL is characterized by loss of function mutations in the Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val, G17V) in the RHOA small GTPase gene Moreover, RHOA G17V expression in Tet2 deficient hematopoietic progenitors resulted in the specific development of lymphoid tumors resembling human AITL. Notably, inhibition of ICOS signaling impaired the growth of RHOA G17V-induced mouse lymphomas in vivo, thus providing a potential new rational approach for the treatment of AITL. Overall design: We analyzed mRNA expression profiles of primary tumor cells expressing Rhoa G17V or Rhoa wild type.
Publication Title
RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the 17~92 cluster of miRNAs is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo1,2. Clinical use of these findings hinges on isolating the oncogenic activity within the 17~92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1 induced T-cell lymphoblastic leukaemia (T-ALL) in vivo. Consistent with the pathogenic importance of this interaction, we report a novel translocation targeting the 17~92 miRNA cluster coinciding with a second rearrangement that activates Notch1 in T-ALL. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short-hairpin RNA (shRNA) screen for genes whose knockdown could phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and included Bim (Bcl2L11)1,3, AMP-activated kinase (Prkaa1), and the tumour suppressor phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clamp down on several regulators of PI3K-related survival signals by the leukaemogenic miR-19.
Publication Title
Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia.
Sample Metadata Fields
Cell line
View Samples