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Series GSE132233 Query DataSets for GSE132233
Status Public on Jun 06, 2019
Title Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enables preclinical screening of compounds against metastatic OS cells in the context of the native lung microenvironment. Using this strategy to screen a library of epigenetically-targeted compounds, we identified inhibitors of CDK12 to be most effective, reducing OS cell outgrowth in the lung by >90% at sub-micromolar doses. CDK12 inhibition led to defects in transcription elongation in a gene length- and expression-dependent manner. These effects were accompanied by defects in RNA processing and altered the expression of genes involved in transcription regulation and the DNA damage response. We further identify OS models that differ in their sensitivity to CDK12 inhibition in the lung and provide evidence that upregulated MYC levels may mediate these differences. Our studies provide a framework for rapid preclinical testing of compounds with anti-metastatic activity and highlight CDK12 as a potential therapeutic target in osteosarcoma.
Overall design H3K27ac, RNA Pol 2, RNA Pol 2 Ser2, and CDK12 CHIP-seq were done for DMSO and E9 treated MG63.3-GFP and 143B-GFP osteosarcoma cells. Whole Genome Sequencing was done for the MG63.3-GFP and 143B-GFP cell lines. Finally, RNA-seq was done on DMSO or E9 treated MG63.3-GFP and 143B-GFP cells in triplicate.
Contributor(s) Bayles I, Saiakhova A, Scacheri PC
Citation(s) 31498151
Submission date Jun 05, 2019
Last update date Sep 11, 2019
Contact name Peter Scacheri
Phone 216-368-3458
Organization name Case Western Reserve University
Street address 10900 Euclid Ave; BRB 647
City Cleveland Heights
State/province OH
ZIP/Postal code 44106
Country USA
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (34)
GSM3854537 143B_DMSO_treated: H3K27ac ChIP Seq
GSM3854538 143B_DMSO_treated: CDK12 ChIP Seq
GSM3854539 143B_DMSO_treated: Pol II Ser2 ChIP Seq
BioProject PRJNA546568
SRA SRP200511

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Supplementary file Size Download File type/resource
GSE132233_RAW.tar 2.6 Gb (http)(custom) TAR (of BROADPEAK, BW, TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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