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GSE150909
Homo sapiens
9 Downloadable Samples
Affymetrix Clariom S Human array (clariomshuman)
Description
Genomic instability predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high-degree of genomic instability remains unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells- the precursor cell type for the majority of high-grade serous ovarian cancers- through the inhibition of RB1 and simultaneously drives a cell protective inhibition of the stimulator-of-interferon-genes (STING) in order to maintain a microenvironment conducive to the propagation of cells with a high-degree of genomic instability. We found that miR-181a inhibition of RB1 leads to profound nuclear defects, genomic instability, and nuclear rupture resulting in a persistence of genomic material in the cytoplasm. While normally, this persistence of genomic material in the cytoplasm induces interferon response through STING to drive cell death, miR-181a directly downregulates STING and prevents apoptosis. The most common mechanism by which oncogenic miRNAs promote tumorigenesis is through the direct inhibition of tumor suppressor genes, however our studies highlight a new mechanism of oncomiR transformation through the combination of tumor suppressor gene inhibition and abrogation of immune surveillance that initiates and propagates tumor cell survival. Importantly, we found that miR-181a induction in ovarian patient tumors is tightly associated with decreased IFNg response and downregulation of lymphocyte infiltration amd leukocyte fraction. To date, DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation thus, our findings are the first to identify a genetic factor, miR-181a, that can downregulate STING expression, suppress activation of the immunosurveillance machinery, and impair signaling in cancer cells creating a survival advantage. Our studies support the notion that the induction of STING-mediated signaling in cancer cells could lead directly to cancer cell death however these effects are abrogated by miR-181a. Given the recent interest in the development of STING agonists as a strategy to harness the immune system to treat cancer, this study introduces novel patient selective biomarker as well as potent therapeutic target for development of the most effective combination treatments.
Publication Title
miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
Illumina HiSeq 4000
Description
The design of selective small-molecules is often stymied by similar ligand binding pockets. Here we report the first cyclin-dependent kinase 6 (CDK6) degrader, BSJ-03-123, that uses phthalimide-conjugation to exploit protein-interface determinants to achieve proteome-wide degradation selectivity. Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and coupling acute degradation with transcriptomics and phosphoproteomics enabled dynamic mapping of the immediate role of CDK6 in coordinating signaling and transcription. Overall design: RNA-seq of MV4-11 cells treated for 6h with the CDK4/6 inhibitor palbociclib or the CDK6-specific phthalimide conjugates BSJ-03-123 and YKL-06-102
Publication Title
Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 29 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a), Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a), Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profiling was performed on primary human erythroid progenitor cells expressing a control shRNA (luciferase), two different HDAC1 shRNAs, and two different HDAC2 shRNAs.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 10 Downloadable Samples
- NextSeq 500
Description
We performed RNA-seq analysis of polA transcripts in IMR-32 cells with shRNA-mediated depletion of CDK12 and CDK13 and GFP as a control Overall design: Expression of polA transcripts in IMR-32 cells with shRNA-mediated depletion of CDK12 and CDK13 using the RNA-seq library kit (QuantSeq 3' mRNA Sequencing REV, Lexogen) using 2 different shRNA constructs for each target in duplicate, for a total of 10 individual samples Please note that processed data files were generated from the merged replicates, as indicated in the corresponding sample description field.
Publication Title
CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profiling was performed on primary human erythroid progenitor cells left untreated or treated with 2uM NK57 for 3 days.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 8 Downloadable Samples
- NextSeq 500
Description
We performed RNA-seq analsysis of polA transcripts in Kelly and Kelly E9 resistant (E9R) cells treated with THZ531 for 6h and DMSO as a control Overall design: Expression of polA transcripts in Kelly and Kelly E9R cells treated with THZ531 using the RNA-seq library kit (QuantSeq 3' mRNA Sequencing REV, Lexogen) in duplicate, for a total of 8 indyvidual samples Please note that the bigWig processed data was generated from both replicates and is linked to the corresponding rep1 (*_1) sample records.
Publication Title
CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
Gene expression profiling was performed on primary human erythroid progenitor cells left untreated or treated with 0.5uM SAHA.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- NextSeq 500
Description
We performed RNA-seq analsysis of polA transcripts in IMR-32 cells treated with THZ531 for 2 and 6h and DMSO as a control Overall design: Expression of polA transcripts in IMR-32 treated with THZ531 using the RNA-seq library kit (QuantSeq 3' mRNA Sequencing REV, Lexogen) in duplicate, for a total of 6 individual samples
Publication Title
CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Homo sapiens
- 87 Downloadable Samples
- Illumina HiSeq 2000
Description
Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. Overall design: RNA-seq in tumor cell lines treated with targeted therapies and/or transcriptional inhibitors
Publication Title
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.
Sample Metadata Fields
Specimen part, Cell line, Subject, Compound
View Samples