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CRISPR/Cas9-Mediated Highly Efficient Gene Targeting in Embryonic Stem Cells for Developing Gene-Manipulated Mouse Models
Published on: August 24, 2022
Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
Ivo J Huijbers1, Rahmen Bin Ali, Colin Pritchard
1Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract:
Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.
Insights
Genetically Engineered Mouse Models (GEMMs) accelerate cancer research by enabling rapid generation of tumor cohorts. This new method efficiently validates cancer genes and drug targets, identifying MycL1 as a key driver in Small Cell Lung Cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genetically Engineered Mouse Models (GEMMs) offer mechanistic insights into cancer development and drug target validation.
- The complexity of GEMMs has historically limited their utility in preclinical studies.
- A need exists for faster, more reliable methods to generate tumor cohorts for cancer gene assessment.
Purpose of the Study:
- To develop a streamlined approach for generating tumor cohorts using GEMMs.
- To overcome the limitations of complex GEMMs in preclinical cancer research.
- To validate the utility of this approach for cancer gene discovery and drug target validation.
Main Methods:
- Derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs.
- Introduction of transgenes into GEMM-ESCs via Flp recombinase-mediated integration.
- Direct utilization of chimeric animals derived from GEMM-ESCs to form tumor cohorts.
Main Results:
- A novel, efficient system for the rapid generation of tumor cohorts from GEMMs was established.
- Stringent quality controls ensure the reliability and effectiveness of the GEMM-ESC approach.
- MycL1 was identified as a key driver gene in Small Cell Lung Cancer, demonstrating proof-of-principle.
Conclusions:
- The GEMM-ESC approach significantly accelerates cancer gene assessment and drug target validation.
- This method provides a reliable platform for preclinical cancer research.
- MycL1 represents a potential therapeutic target in Small Cell Lung Cancer.
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