Related Experiment Video
Updated: Apr 20, 2026
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
An autochthonous CRISPR activation screening platform for characterizing tissue-specific oncogene selection
Fredrik I Thege1, Amber Hoskins2, Annaliese Kramer2
1Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
In vivo CRISPR activation screening successfully models oncogene selection in lung and pancreas cancers. This approach reveals tissue-specific gene dependencies crucial for tumor initiation and progression.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Human adenocarcinomas display unique mutation and copy-number profiles, indicating varied selective pressures and oncogene dependencies.
- Understanding these tissue-specific patterns is key to deciphering tumor initiation and progression.
Purpose of the Study:
- To evaluate the efficacy of in vivo CRISPR activation screening (CRISPRa) in recapitulating oncogene selection during tumor initiation.
- To identify frequently amplified and mutated genes in autochthonous lung and pancreas cancer models.
Main Methods:
- Utilized CRISPRa-competent PPKS mice for in vivo screening.
- Administered pooled lentivirus via intranasal or intraductal delivery.
- Screened frequently amplified and mutated genes in lung and pancreas cancer models.
Main Results:
- Observed strong selection for Egfr, Myc, Sox2, and Pik3cb activation in lung tumors.
- Demonstrated near-complete dominance of Myc activation in pancreatic tumors, highlighting tissue-specific differences.
- Sox2 activation suppressed Nkx2-1 signaling, driving mucinous lung adenocarcinoma.
- MYC activation in pancreatic tumors mirrored human PDAC amplification and led to an immune-cold microenvironment.
Conclusions:
- In vivo CRISPR activation screening accurately captures oncogene selection during tumor initiation.
- This screening method offers a powerful tool for investigating tumor initiation and progression mechanisms.
- Findings underscore the critical role of tissue-specific oncogene dependencies in adenocarcinoma development.
