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SRP053098
Homo sapiens
4 Downloadable Samples
IlluminaGenomeAnalyzerIIx
Description
The c-MYC oncogene is a key transcription factor deregulated in most human tumors. Histone marks associated with transcriptionally active genes in euchromatic islands define the set of high-affinity c-MYC targets. The mechanisms involved in their recognition by c-MYC are not known but likely involve chromatin-remodelling and chromatin-modifying complexes. Here, we show that c-MYC interacts with BPTF, a core subunit of the NURF complex that binds active chromatin. BPTF is required for the activation of the full c-MYC transcriptional programme in fibroblasts. BPTF knockdown leads to a decrease in c-MYC recruitment to DNA and to changes in chromatin accessibility. Using BPTF-null MEFs we show that BPTF is necessary for c-MYC-driven proliferation, G1-S progression, and replication stress, but not for c-MYC-driven apoptosis. Consistently, BPTF is required for the proliferation of cells driven by c-MYC, such as Burkitt lymphoma, and its expression in human cancer lines correlates with the activation of c-MYC gene signatures. Our findings point to the c-MYC-BPTF axis as a potential therapeutic target in cancer. Overall design: To assess whether BPTF is required for the transcriptional activity of c-MYC, human foreskin fibroblasts (HFF) were stably transduced with the chimeric MYC-ER cDNA (HFF MYC-ER) and infected with lentiviruses coding for either control (shNt) or BPTF-targeting shRNAs. Cells were serum-starved for 2 days to achieve quiescence and then treated with 4-hydroxytamoxifen (4-OHT)
Publication Title
BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- IlluminaGenomeAnalyzerIIx
Description
Choline kinase alpha (CHKA) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKA in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKA expression and a good correlation between protein expression and sensitivity to MN58b, a CHKA inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKA knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKA inhibition and, in vitro, MN58b had synergistic effects with gemcitabine, 5-fluorouracil and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKA was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKA did not relate to survival, nuclear CHKA distribution was observed in 43% of samples and was associated with survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKA inhibitors, we cultured IMIM-PC-2 cells with continuous incremental concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified up-regulation of ABCB1 and ABCB4 multidrug resistance transporters and functional studies confirmed that their up-regulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKA inhibition merits further attention as a therapeutic option in patients with PDAC. Overall design: RNA profile from parental and MN58b-resistant IMIM-PC-2 were generated by deep sequencing were done in triplicates using illumina GAIIx
Publication Title
Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Choline kinase a (CHKa) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKa in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKa expression, associated with differentiation. CHKa protein expression was directly correlated with sensitivity to MN58b, a CHKa inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKa knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKa inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKa was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKa did not relate to survival, nuclear CHKa distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKa inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKa inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response. Overall design: RNAseq from parental (IMIM-PC2 cell line)) and MN58b-resistant cells by triplicate
Publication Title
Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The role of SPROUTY2 (SPRY2) in human colon cancer is controversial. Our data support a tumorigenic action of SPRY2. We use microarrays to identify SPRY2 target genes in human SW480 ADH colon carcinoma cell line.
Publication Title
SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
A cancer stem cell cannot be identified solely based on surface markers as none of the markers used to isolate stem cells in various normal and cancerous tissues is expressed exclusively by stem cells. Our experimental results have also identified additional fractions representing true stem-like cells in oral squamous cell carcinoma (OSCC), refuting the concept that cancer stem cells (CSCs) are a rare population, and we have also developed an in vitro model to explore the stem cell concept in oral epithelial tumorigenesis. This model expounds four distinct fractions within a homogenous cell line SCC172 that is morphologically similar (85% cells expressing CSC markers), yet varying in all functional aspects of cell cycle, dye retention, chemoresistance, tumor-forming potential, self renewal, apoptosis resistance and regulation at molecular levels. Relating to our CSC shift model, we analysed the concept of biological heterogeneity in terms of four fractions SP1, SP2, MP1 and MP2 and associated it with variations among patients in a clinical scenario.
Publication Title
Analysis of MicroRNA-mRNA Interactions in Stem Cell-Enriched Fraction of Oral Squamous Cell Carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Schizosaccharomyces pombe
- 6 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Spc1/ Spc1K49R was overexpressed in wt S. pombe cells for 24 hours and gene expression changes were analysed
Publication Title
Genome wide transcription profiling of the effects of overexpression of Spc1 and its kinase dead mutant in Schizosaccharomyces pombe.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Rattus norvegicus
- 13 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Multi-tissue regenerative capacity is lost in adult mammals with the exception of the distal digit, which regenerates via largely-uncharacterized mechanisms. Here, we demonstrate that following adult mouse distal digit removal, nerve-associated Schwann cell precursors (N-SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. Specifically, when N-SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased, nail and bone regeneration were impaired, and regeneration could be rescued by transplantation of exogenous N-SCPs. We show that N-SCPs secreted factors that promoted self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and PDGF-AA, were made by N-SCPs in the regenerating digit, and rescued the deficits in regeneration caused by loss of N-SCPs due to denervation. Since nerves innervate every peripheral tissue, these results have broad implications for mammalian tissue repair and regeneration.
Publication Title
Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip.
Sample Metadata Fields
Treatment
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Multi-tissue regenerative capacity is lost in adult mammals with the exception of the distal digit, which regenerates via largely-uncharacterized mechanisms. Here, we demonstrate that following adult mouse distal digit removal, nerve-associated Schwann cell precursors (N-SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. Specifically, when N-SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased, nail and bone regeneration were impaired, and regeneration could be rescued by transplantation of exogenous N-SCPs. We show that N-SCPs secreted factors that promoted self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and PDGF-AA, were made by N-SCPs in the regenerating digit, and rescued the deficits in regeneration caused by loss of N-SCPs due to denervation. Since nerves innervate every peripheral tissue, these results have broad implications for mammalian tissue repair and regeneration.
Publication Title
Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 49 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
This work was conducted to identify shared and specific target genes of different ETS transcription factor rearrangements in prostate cancer. Potential target genes were identified by differential gene expression analysis of primary tumor samples with ETS rearrangements, and validated by ETS silencing in prostate cancer cell lines.
Publication Title
Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements.
Sample Metadata Fields
Specimen part
View Samples