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GSE135463
Mus musculus
15 Downloadable Samples
Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia while excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although Sonic Hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms down-regulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which down-regulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling. In striking contrast, we found that co-deleting Gsk-3α and Gsk-3β blocked CGNP proliferation, causing severe cerebellar hypoplasia. Transcriptomic analysis showed activated WNT signaling and up-regulated Cdkn1a in Gsk-3-deleted CGNPs. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathologic growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.
Publication Title
GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Patients with medulloblastoma are typically treated with a narrow range of therapies, but may experience widely divergent outcomes; 80-90% become long-term survivors while 20% develop incurable recurrence. Transcriptomic profiling has identified four subgroups with different recurrence risks, but outcomes remain variable for individual patients within each subgroup. To gain new insight into why patients with similar-appearing tumors have variable outcomes, we examined how the timing of tumor initiation effects medulloblastomas triggered by a single, common driver mutation. We genetically-engineered mice to express an oncogenic Smo allele starting early in development in the broad lineage of neural stem cells, or later, in the more committed lineage of cerebellar granule neuron progenitors. Both groups developed medulloblastomas and no other tumors. We compared medulloblastoma progression, response to therapy, gene expression profile and cellular heterogeneity, determined by single cell transcriptomic analysis (scRNA-seq). The average transcriptomic profiles of the tumors were similar. However, stem cell-triggered medulloblastomas progressed faster, contained more OLIG2-expressing tumor stem cells, and consistently showed radioresistance. In contrast, progenitor-triggered MBs progressed slower, lost stem cell character over time and were radiosensitive. Progenitor-triggered medulloblastomas also contained more diverse stromal populations, including tumor-associated macrophages, indicating that the timing of oncogenesis affected the subsequent interactions between the tumor and microenvironment. Our findings show that developmental events in tumorigenesis may be impossible to infer from transcriptomic profile, but while remaining cryptic can nevertheless influence tumor composition and the outcome of therapy. Precise understanding of medulloblastoma pathogenesis and prognosis requires supplementing transcriptomic data with biomarkers of cellular heterogeneity.
Publication Title
Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 15 Downloadable Samples
Illumina HiSeq 4000
Description
Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq, we analyzed cellular diversity and lineage in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. Overall design: Drop-Seq single-cell transcriptome sequencing of 15 mice: 5 Wild Type cerebella, 5 Drug-treated cerebellar tumors and 5 vehicle-treated cerebellar tumros.
Publication Title
scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
To gain insights into the mechanism responsible for the protumorigenic actions of NRG we performed gene expression analyses of MCF7 cells treated with soluble NRG for 3, 6, 12 and 24 hours.
Publication Title
Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node.
Sample Metadata Fields
Age, Specimen part, Disease, Cell line, Treatment, Time
View Samples- Mus musculus
- 36 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Differential gene expression assessed in siTNF-OMe-P treated animals showed significant correlation between improved colon integrity and clinical parameters of colitis with reduced TLR activation, tissue regeneration and reduced pro-inflammatory cytokines, as compared to all treatment groups.
Publication Title
Functionally enhanced siRNA targeting TNFα attenuates DSS-induced colitis and TLR-mediated immunostimulation in mice.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
To investigate downstream targets of PRRX1, we used MDA-MB-231 (MDA231) breast cancer cells which express low level of PRRX1 to generate a stable cell line where human PRRX1 was ectopically overexpressed
Publication Title
A gene regulatory network to control EMT programs in development and disease.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 246 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Gene expression profiles of paired normal adjacent mucosa and tumor samples from 98 individuals and 50 healthy colon mucosae, were obtained through Affymetrix Human Genome U219 Arrays. This dataset is in the context of the COLONOMICS project and to query additional information you can visit the project website www.colonomics.org.
Publication Title
Discovery and validation of new potential biomarkers for early detection of colon cancer.
Sample Metadata Fields
Sex, Age, Disease, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is a mind aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Gene set enrichment analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
Publication Title
Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples- Rattus norvegicus
- 2 Downloadable Samples
- Illumina HiSeq 2500
Description
Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here, we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c, and their protein targets smarca5 and fntb, as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response following myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof-of-concept for identifying and activating conserved molecular programs to regenerate the damaged heart. Overall design: RNA-Seq expression profiles of rat cardiomyocytes after knockdown of miR-99/100 and Let-7 miRNAs
Publication Title
In vivo activation of a conserved microRNA program induces mammalian heart regeneration.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Establishment of human iPSC-based models for the study and targeting of glioma initiating cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples