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SRP137093
Mus musculus
143 Downloadable Samples
Illumina HiSeq 2500, Illumina HiSeq 2000
Description
Cancer-associated inflammatory processes in the tumour microenvironment, as well as systemically, are strongly linked with poor disease outcome in cancer patients. For most human solid tumour types, high systemic neutrophil-to-lymphocyte ratios (NLR) are associated with increased metastasis and poor overall survival and recent experimental studies have demonstrated a causal relationship between neutrophils and metastasis formation. However, to date, the cancer cell-intrinsic mechanisms dictating the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Using a panel of 16 distinct genetically engineered mouse models (GEMMs) for breast cancer, we demonstrate that tumour cell-intrinsic loss of p53 changes the phenotype and function of macrophages in the microenvironment, leading to activation of a systemic inflammatory cascade that drives neutrophil expansion. Mechanistically, p53 loss in cancer cells induces secretion of Wnt ligands that act in a paracrine fashion to stimulate IL-1b production from tumour-associated macrophages. Intratumoural IL-1ß production stimulates an inflammatory cascade leading to the systemic accumulation of neutrophils. Pharmacological and genetic blockade of cancer cell-derived Wnt secretion reverses IL-1ß expression by macrophages and subsequent systemic neutrophilic inflammation. Collectively, using pre-clinical mouse models for breast cancer, we demonstrate a novel mechanistic link between loss of p53 in cancer cells, Wnt ligand secretion and systemic immune activation. This illustrates the importance of cancer cell-intrinsic genetic aberrations in dictating cancer-associated inflammation. These insights set the stage for personalized immune intervention strategies for cancer patients. Overall design: In this study, gene expression profiles of tumours from genetically engineered mouse models (GEMMs) were analysed using RNA sequencing. Analysis was performed on bulk tumours of 10 GEMMs with different tissue-specific mutations driving tumorigenesis, totalling to 125 different tumours (n=5 or more per group). Subsequently, samples were grouped according to p53 status of the tumour (models containing Trp53 floxed alleles, or not) and comparisons were made between p53-KO and p53-WT tumours.
Publication Title
Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 27 Downloadable Samples
- IlluminaHiSeq2500
Description
Compound Kushen Injection (CKI) has been clinically used in China for over 15 years to treat various types of solid tumours. However, because such Traditional Chinese Medicine (TCM) preparations are complex mixtures of plant secondary metabolites, it is essential to explore their underlying molecular mechanisms in a systematic fashion. We have used the MCF-7 breast cancer cell line as an initial in vitro model to identify CKI induced changes in gene expression. Cells were treated with CKI for 24 and 48 hours at two concentrations (1.0 and 2.0 mg/mL), and 5-Fluorouracil (5-FU) was used to treat cells as a positive control. Cell proliferation and apoptosis activity were measured with XTT and Caspase-3 assays respectively. Transcriptome data of cells treated with CKI or 5-FU for 24 and 48 hours were acquired using high-throughput Illumina RNA-seq technology. In this report we show that CKI inhibited MCF-7 cell proliferation and induced apoptosis in a dose-dependent fashion. We integrated and applied a series of transcriptome analysis methods, including gene differential expression analysis, pathway over-representation analysis, de novo identification of long non-coding RNAs (lncRNA) as well as co-expression network reconstruction, to identify candidate anti-cancer molecular mechanisms of CKI. Multiple pathways were perturbed and the cell cycle was identified as the potential primary target pathway of CKI in MCF-7 cells. CKI may also induce apoptosis in MCF-7 cells via a p53 independent mechanism. In addition, we identified novel lncRNAs and showed that many of them might be expressed as a response to CKI treatment. Overall, we have comprehensively investigated the utility of transcriptome analysis with high-throughput sequencing to characterise the molecular response of cancer cells to a TCM drug, and provided a practical guideline for future molecular studies of TCM. Overall design: High-depth paired-end RNA-seq from MCF-7 cell line. Each sample contains 3 biological replicates.
Publication Title
Identification of candidate anti-cancer molecular mechanisms of Compound Kushen Injection using functional genomics.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and of its proteolytic fragments are still poorly understood. The secreted APPs ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The -secretase generated APP intracellular domain, AICD, functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial. Previously, we have generated APPs knockin (KI) mice expressing solely the secreted ectodomain APPs. Here, we generated double mutants (APPs-DM) by crossing APPs-KI mice onto an APLP2-deficient background and show that APPs rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPs-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP. To gain further mechanistic insight into which domains/proteolytic fragments are crucial for hippocampal APP/APLP2 mediated functions, we performed a DNA microarray transcriptome profiling of prefrontal cortex and hippocampus of adult APLP2-KO (APLP2-/-) and APPs-DM mice (APP/APLP2-/- mice).Interestingly, this analysis failed to reveal major genotype-related transcriptional differences. Expression differences between cortex and hippocampus were, however, readily detectable.
Publication Title
APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2500
Description
The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs of both mouse and man. We previously demonstrated that Treg induced in peripheral sites (pTreg) from Foxp3- T conventional (Tconv) cells were Helios- and proposed that Helios is a marker of thymic derived Treg (tTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype and had a higher suppressive capacity in vitro. Both populations expressed a highly demethylated TSDR and both subsets were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios- Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios- Treg when transferred to lymphopenic mice. Gene expression profiling of the two populations demonstrated a large number of differentially expressed genes and that Helios- Treg subpopulation expressed certain genes normally expressed in CD4+Foxp3- T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios- Treg. Thus, Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct, consistent with thymic and peripheral sites of origin, respectively. Because of their superior suppressive activity and enhanced stability Foxp3+Helios+ Treg represent the optimal Treg population for cellular immunotherapy. Overall design: 5 replicates of wildtype vs knockout Helios gene in Treg cells.
Publication Title
Helios<sup>+</sup> and Helios<sup>-</sup> Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 75 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Analysis of adult and childhood tumors reveals activation of an E2F3 signature unique to Wilms tumors.
Publication Title
The E2F3-Oncomir-1 axis is activated in Wilms' tumor.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20), Illumina HiSeq 2000
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
Publication Title
Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 36 Downloadable Samples
- Illumina HiSeq 2000
Description
Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level we provide evidence that anle138b blocks the formation of conducting Aß pores without changing the membrane embedded Aß-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further. Overall design: APPdelta9 and Wildtype mouse treated with anle138b or placebo
Publication Title
The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology.
Sample Metadata Fields
Age, Cell line, Subject
View Samples- Mus musculus
- 11 Downloadable Samples
- Illumina HiSeq 2000
Description
Analysis of global gene expression in myeloid cells infiltrating tumors after irradiation. Cell death induces recruitment of myeloid cells into irradiated tumors thereby stimulating tumor recurrence. Results provide insights into molecular mechanisms regulating tumorigenic functions of myeloid cells in tumors re-growing after radiation therapy. Overall design: Samples were collected at day 4 from irradiated tumors in WT, TLR9KO and Stat3KO (MxCre/Stat3flox). There were total 11 samples with  3-4 replicates of each sample type.
Publication Title
TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- IlluminaGenomeAnalyzerIIx
Description
In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. Overall design: RNA-Seq Experiments in 2 different primary breast epithelial cell lines (HMLE, which were sorted according to CD44/CD24 surface markers & unsorted IMEC). Both cell lines expressed a doxycycline-inducible version of MYC. For the HMLE cell line DGE analysis was performed for the uninduced (EtOH) situation, comparing CD44high vs CD44 low and for the induced situation Dox vs. EtOH for the CD44high population. For the IMEC cell line DGE was performed by comparing Dox-treated populations expressing either Dox-inducible MYC or a vector control which allows to filter out potential effects due to doxycycline treatment.
Publication Title
A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer.
Sample Metadata Fields
No sample metadata fields
View Samples