Related Experiment Video
Updated: Jan 19, 2026
Practical Considerations in Studying Metastatic Lung Colonization in Osteosarcoma Using the Pulmonary Metastasis Assay
Published on: March 12, 2018
Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma
Ian Bayles1, Malgorzata Krajewska2, W Dean Pontius1
1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
Abstract:
Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enabled 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 more than 90% at submicromolar doses. We found that knockout of CDK12 in an in vivo model of lung metastasis significantly decreased the ability of OS to colonize the lung. 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 identified OS models that differ in their sensitivity to CDK12 inhibition in the lung and provided evidence that upregulated MYC levels may mediate these differences. Our studies provided a framework for rapid preclinical testing of compounds with antimetastatic activity and highlighted CDK12 as a potential therapeutic target in OS.
Insights
New preclinical models reveal CDK12 inhibitors significantly reduce osteosarcoma (OS) lung metastasis. Targeting CDK12 offers a promising therapeutic strategy for this aggressive bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Outcomes for metastatic osteosarcoma (OS) remain poor despite treatment advances.
- There is a critical need for novel therapeutic strategies targeting OS metastasis.
Purpose of the Study:
- To develop a preclinical model for screening anti-metastatic compounds in OS.
- To identify novel therapeutic targets for osteosarcoma lung metastasis.
Main Methods:
- Developed a system for preclinical screening of compounds against metastatic OS cells within the lung microenvironment.
- Screened epigenetically targeted compounds, focusing on CDK12 inhibitors.
- Utilized in vivo models to assess the efficacy of CDK12 inhibition on OS lung colonization.
Main Results:
- CDK12 inhibitors reduced OS cell outgrowth in the lung by over 90% at submicromolar doses.
- CDK12 knockout significantly decreased OS lung colonization in vivo.
- CDK12 inhibition caused transcriptional defects, RNA processing issues, and altered DNA damage response gene expression.
- Identified differential sensitivity to CDK12 inhibition, potentially mediated by MYC levels.
Conclusions:
- CDK12 is a promising therapeutic target for osteosarcoma lung metastasis.
- The developed preclinical system facilitates rapid testing of anti-metastatic compounds.
- Further investigation into MYC's role in CDK12 inhibitor sensitivity is warranted.
Related Concept Videos
07:44Practical Considerations in Studying Metastatic Lung Colonization in Osteosarcoma Using the Pulmonary Metastasis Assay
04:25Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
08:04Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
10:00In Vivo Forward Genetic Screen to Identify Novel Neuroprotective Genes in Drosophila melanogaster
08:52Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells
13:04In Vivo and Ex Vivo Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose