The PI3K/mammalian target of rapamycin (mTOR) pathway is dysregulated in over 50% of human GBM but remains a challenging clinical target. Inhibitors against PI3K/mTOR mediators have limited clinical efficacy as single agents. Gene expression profiling after PI3K/mTOR inhibition treatment was analyzed by Affymetrix microarrays.
MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma.
Specimen part, Cell line
View SamplesMultipotent stem cells and their lineage-restricted progeny drive nephron formation within the developing kidney. Validated markers of these early stem/progenitor populations are essential for deciphering their in vivo function and for evaluating their clinical potential for treating adult kidney disease. Here, we document expression of the adult stem cell marker Lgr5 in the developing kidney and assess the stem/progenitor identity of Lgr5+ve cells via in vivo lineage tracing. The appearance and localization of Lgr5+ve cells coincided with that of the S-shaped body around E14. Lgr5 expression remained restricted to cell clusters within developing nephrons in the cortex until P7, when expression was permanently silenced. In vivo lineage tracing identified Lgr5 as a marker of a novel progenitor population within nascent nephrons dedicated to generating the thick ascending limb of Henle's loop and distal convoluted tubule. The Lgr5 surface marker and experimental models described here will be invaluable for deciphering the contribution of early nephron stem cells to developmental defects and for isolating human nephron progenitors as a prerequisite to evaluating their therapeutic potential.
Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development.
Specimen part
View SamplesThe pretreatment karyotype of leukemic blasts is currently the key determinant in therapy decision-making in acute myeloid leukemia (AML). However, approximately fifty percent of AML patients, often carrying a normal karyotype, are currently unclassifiable based these established methods. Gene expression profiling has proven to be valuable for risk stratification of AML.
Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesInterleukin-6 (IL-6) is an important growth factor for estrogen receptor-alpha (ER) positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. We firstly demonstrated that pSTAT3 is the primary downstream IL-6 signaling pathway in ER-positive breast cancer, using ten different breast cancer cell lines. Three-dimensional cultures of these cell lines were also used to develop a 17-gene IL-6 specific gene signature that could be used to identify IL-6 driven disease. This signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. To further validate this IL-6 signature, we obtained 36 human ER-positive breast cancer tumor samples with matched serum for gene expression profiling and determination of an IL-6 pathway activation score (PAS). Patients with high IL-6 PAS were also enriched for elevated serum IL-6 (>=10 pg/ml). We then utilized a murine MCF-7 xenograft model to determine the role of IL-6 in ER-positive breast cancer and potential anti-IL-6 therapy in vivo. When IL-6 was administered in vivo, MCF-7 cells engrafted without the need for estrogen supplementation. Subsequently, we prophylactically treated mice at MCF-7 engraftment with an anti-IL-6 antibody (siltuximab), fulvestrant or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, when tumors were allowed to grow to 125 mm3 before treatment, siltuximab alone demonstrated tumor regressions in 90% (9/10) of tumors. Given the established role for IL-6 in ER+ breast cancer, this data demonstrates the potential for anti-IL-6 therapeutics.
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer.
Specimen part
View SamplesBackground: Castration-resistant prostate cancer (CRPC) represents a therapeutic challenge for current medications.
Integrative genomic, transcriptomic, and RNAi analysis indicates a potential oncogenic role for FAM110B in castration-resistant prostate cancer.
Sex, Specimen part, Disease, Disease stage, Cell line, Treatment, Race
View SamplesAs the list of putative driver mutations in glioma grows, we are just beginning toAs the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous, glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.
Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma.
No sample metadata fields
View SamplesTo identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes and ectopic NKX2-1 or NKX2-2 expression for which rearrangements were identified. The second subtype associated with immature T-cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C or MEF2C-associated cofactors. We propose NKX2-1, NKX2-2 and MEF2C as T-ALL oncogenes that are activated by various rearrangements.
Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma.
Specimen part, Cell line
View SamplesMicro RNAs (miRNAs) miR-130a, miR-203 and miR-205 are jointly downregulated in prostate cancer and act as repressors of AR-signaling. MiRNAs are small non-coding RNAs that regulate the expression of specific mRNA targets mainly by translational repression, mRNA deadenylation or cleavage. Reconstitution of these lost miRNAs in the LNCaP PCa cell line cause morphology changes, growth arrest, and apoptosis, increasing when the miRNAs were co-expressed. This series identifies direct targets of miR-130a, miR-203, and miR-205 by AGO2-RNA co-immunoprecipitation as described by (Beitzinger et al. 2007) upon miRNA reconstitution in LNCaP cells and analyzing AGO2-bound mRNAs using Affymetrix Genechips. Relative levels of AGO2 bound versus total RNA expression were compared between miRNA reconstituted and miR-scr transfected samples.
MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma.
Specimen part, Cell line
View SamplesMicro RNAs (miRNAs) miR-130a, miR-203 and miR-205 are jointly downregulated in prostate cancer and act as repressors of AR-signaling. MiRNAs are small non-coding RNAs that regulate the expression of specific mRNA targets mainly by translational repression, mRNA deadenylation or cleavage. Reconstitution of these lost miRNAs in the LNCaP PCa cell line cause morphology changes, growth arrest, and apoptosis, increasing when the miRNAs were co-expressed. Bioinformatic target prediction, mRNA expression and protein expression analysis upon overexpression of these miRNAs congruently identified targets known to be overexpressed in PCa and to be involved in AR trans-activation. This series profiles loss in mRNA expression in LNCaP cells transfected with one of the three miRNAs miR-130a, miR-203 and miR-205 compared to LNCaP cells transfected with a scramble miRNA.
MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma.
Cell line
View Samples