Related Experiment Video
Updated: May 12, 2026
Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
Published on: August 25, 2023
Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome
J Bhadury1, M D López, S V Muralidharan
1Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
Abstract:
Cancer development occurs in response to the successive accumulation of mutations that eventually targets key regulators of cell proliferation. As most mutations likely occur randomly, cancer driver mutations can only be found if they are recurrent. Here we use exome sequencing of the mouse cell lines Panc02, L1210 and Colon 26 to identify genetic alterations (single-nucleotide polymorphisms and small insertion and deletions) that occurred in three different strains of mice and that resulted in tumorigenesis. We identify known mutations in genes like Kras, Cdkn2a/b, Smad4 and Trp53 and a large list of genes whose causal link to cancer is unknown. Interestingly, by screening a compound library we find that the identified oncogenic Kras mutation in Colon 26 cells correlates with its sensitivity to MEK inhibitors in vitro and in vivo. Our analysis of these mouse tumor exomes show that their manageable number of mutations could facilitate the identification of novel mutations or pathways driving tumor development. Furthermore, their use as tools is now enhanced as they can be used to create syngenic transplant models for utilization in drug discovery and validation. Finally, by showing that Kras mutant Colon 26 cells are sensitive to MEK inhibitors, we provide one proof-of-principle experiment that a platform containing targeted resequencing and drug screens could be a valuable addition in the clinic to devise anti-cancer drug schemes.
Insights
This study identifies cancer-driving mutations in mouse models using exome sequencing. Oncogenic Kras mutations in Colon 26 cells show sensitivity to MEK inhibitors, aiding drug discovery.
Area of Science:
- Genomics and Cancer Biology
- Translational Oncology
- Drug Discovery
Background:
- Cancer arises from accumulated mutations affecting cell proliferation regulators.
- Identifying recurrent cancer driver mutations is crucial for understanding tumorigenesis.
- Mouse models offer valuable platforms for studying genetic alterations in cancer.
Purpose of the Study:
- To identify genetic alterations driving tumorigenesis in mouse cell lines.
- To explore the potential of mouse tumor exomes in discovering novel cancer pathways.
- To validate the utility of mouse models in drug discovery and validation.
Main Methods:
- Exome sequencing of Panc02, L1210, and Colon 26 mouse cell lines.
- Identification of single-nucleotide polymorphisms and small insertion/deletions.
- Compound library screening and in vitro/in vivo drug sensitivity assays.
Main Results:
- Identified known mutations in cancer-related genes (Kras, Cdkn2a/b, Smad4, Trp53).
- Discovered a list of novel genes potentially linked to cancer development.
- Demonstrated that Kras-mutant Colon 26 cells are sensitive to MEK inhibitors.
Conclusions:
- Mouse tumor exome analysis facilitates the identification of novel cancer drivers.
- Syngenic transplant models derived from these exomes enhance drug discovery pipelines.
- Targeted resequencing and drug screening platforms can guide personalized anti-cancer therapy.
