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Published on: February 8, 2020
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Novel genetically engineered mouse models for clear cell renal cell carcinoma
Johannes C van der Mijn1,2, Kristian B Laursen1,3,4, Leiping Fu1
1Department of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
Scientific Reports
|May 22, 2023
Summary
Researchers developed two genetically engineered mouse models (GEMMs) to study chromosome 3p deletions in kidney cancer. The models use CRISPR-Cas9 to target key genes, providing a new tool for cancer research and therapy development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) frequently exhibits chromosome 3p deletions.
- Genetically engineered mouse models (GEMMs) are crucial for studying cancer gene function and developing therapies.
- Existing models do not fully recapitulate the extensive 3p deletions seen in human ccRCC.
Purpose of the Study:
- To develop novel GEMMs that model the frequent chromosome 3p deletion in ccRCC.
- To investigate the efficacy of inducible CRISPR-Cas9 systems for gene editing in kidney cancer models.
- To establish spatiotemporally controlled mouse models for studying tumor suppressor gene inactivation in ccRCC.
Main Methods:
- Development of two inducible CRISPR-Cas9 based GEMMs (BPS-TA and BPS-Cre).
- Targeting of Bap1, Pbrm1, and Setd2 tumor suppressor genes using paired or single guide RNAs.
- Utilized tetracycline-responsive elements (TRE3G) and Cre-lox systems for inducible gene editing in specific kidney cell populations.
Main Results:
- The BPS-TA model showed low frequencies of somatic mutations in Bap1 and Pbrm1, with no detectable tissue transformation.
- RNAseq analysis of BPS-TA kidneys revealed activation of DNA damage and immune response pathways.
- The BPS-Cre model demonstrated increased gene-editing frequencies for Pbrm1 and extensive editing of Setd2, unlike the BPS-TA model.
Conclusions:
- This study reports the first GEMMs modeling extensive chromosome 3p deletions relevant to kidney cancer.
- The developed models offer spatiotemporal control over gene editing for studying ccRCC pathogenesis.
- Further studies are needed to model more comprehensive 3p deletions and enhance cellular resolution for precise gene inactivation effects.
