Oncology mouse models enable researchers to investigate the genetic drivers of cancer, study tumor microenvironment interactions, and evaluate therapeutic approaches in immunocompetent systems. From conditional tumor suppressor knockouts that initiate tissue specific tumors to oncogene knockins expressing driver mutations at physiological levels, the right model design is critical for understanding cancer biology and developing effective treatments.
Genetically engineered mouse models (GEMMs) provide advantages over transplantation models by recapitulating tumor initiation, progression, and microenvironment interactions in their native context.
Tumor Suppressor Models
Conditional Tumor Suppressor Knockouts
Conditional deletion of tumor suppressors enables controlled tumor initiation in specific tissues:
Conditional approaches prevent embryonic lethality and enable tissue specific tumor initiation that models human cancer development.
Combinatorial Tumor Models
Cancer often requires multiple genetic hits. Combining tumor suppressor deletions accelerates tumor development and better models human cancer genetics:
Common Tumor Suppressor Targets
| Gene | Function | Tumor Types | Common Cre Drivers |
|---|---|---|---|
| Trp53 | Cell cycle, apoptosis | Multiple tumor types | Tissue dependent |
| Rb1 | Cell cycle | Retinoblastoma, SCLC | Tissue dependent |
| Pten | PI3K pathway | Prostate, breast, brain | Probasin, MMTV, Nestin |
| Apc | Wnt pathway | Colorectal, intestinal | Villin, CDX2 |
| Brca1/2 | DNA repair | Breast, ovarian | MMTV, K14 |
| Nf1 | Ras pathway | Neurofibroma, MPNST | Tissue dependent |
| Nf2 | Hippo pathway | Mesothelioma, schwannoma | Tissue dependent |
| Smad4 | TGFβ pathway | Pancreatic, colorectal | Pdx1, Villin |
Oncogene Models
Conditional Oncogene Knockins
Knockin of activated oncogenes at endogenous loci provides physiological expression.
LSL (Lox Stop Lox) System
The LSL system enables conditional oncogene activation:
- Oncogene preceded by LoxP flanked transcriptional stop cassette
- Gene silent until Cre removes stop cassette
- Enables tissue specific and temporal oncogene activation
- Widely used for Kras, Braf, and other oncogene models
| Gene | Mutation | Cancer Types | Activation Strategy |
|---|---|---|---|
| Kras | G12D, G12V, G12C | Lung, pancreatic, colorectal | LSL Cre dependent |
| Braf | V600E | Melanoma, thyroid, colorectal | LSL Cre dependent |
| Egfr | L858R, exon 19 del | Lung adenocarcinoma | Conditional expression |
| Pik3ca | H1047R, E545K | Breast, colorectal | Conditional expression |
| Myc | Overexpression | Lymphoma, multiple types | Tet regulatable |
| Her2/Neu | Activated | Breast cancer | MMTV driven |
Cancer Type Specific Models
Lung Cancer
Models for NSCLC and SCLC
- Kras LSL G12D:Lung adenocarcinoma with SPC Cre or Ad Cre
- Kras G12D + Trp53:Aggressive lung adenocarcinoma
- EGFR mutant knockin:TKI sensitive and resistant models
- Trp53 + Rb1:Small cell lung cancer
Breast Cancer
Models for different breast cancer subtypes
- MMTV PyMT:Luminal breast cancer model
- Brca1/2 conditional knockout:BRCA mutant breast cancer
- Her2 overexpression:HER2 positive breast cancer
- Trp53 + Pten:Triple negative breast cancer model
Pancreatic Cancer
Models for pancreatic ductal adenocarcinoma
- KPC (Kras G12D + Trp53):Standard PDAC model with Pdx1 Cre
- Kras G12D alone:PanIN progression model
- Smad4 conditional knockout:TGFβ pathway in PDAC
Colorectal Cancer
Models for intestinal and colorectal cancer
- Apc Min:Germline Apc mutation, intestinal adenomas
- Apc conditional knockout:Controlled adenoma initiation
- Apc + Kras + Trp53:Invasive colorectal cancer
Hematological Malignancies
Models for leukemia and lymphoma
- MLL fusion knockins:Mixed lineage leukemia
- BCR ABL knockin:CML model
- Myc overexpression:Lymphoma models
- Conditional knockouts:CD19 Cre, Vav Cre for hematopoietic lineages
Immuno Oncology Applications
Syngeneic Compatibility
GEMMs on defined strain backgrounds enable immunotherapy studies:
- Tumors arise in immunocompetent hosts
- Native tumor microenvironment development
- Checkpoint inhibitor efficacy studies
- Combination immunotherapy evaluation
Checkpoint Humanization
Humanized checkpoint models enable testing of clinical antibodies:
- Combine humanized checkpoints with genetic tumor models
- Test anti PD1, anti PDL1, anti CTLA4 in autochthonous tumors
- Evaluate combination approaches
Research Applications
Tumor Biology
- Tumor initiation and progression
- Metastasis mechanisms
- Tumor microenvironment interactions
- Cancer stem cell biology
Target Validation
- Genetic validation of therapeutic targets
- Resistance mechanism identification
- Synthetic lethality studies
- Biomarker discovery
Therapeutic Development
- Targeted therapy efficacy
- Immunotherapy response
- Combination therapy optimization
- Drug resistance modeling
Technical Considerations
Cre Driver Selection
Tissue specific Cre drivers determine tumor location:
- Match Cre driver to desired tumor site
- Consider timing of Cre expression
- Evaluate penetrance and specificity
- Inducible Cre enables controlled tumor initiation
Strain Background
Strain background affects tumor biology and immunotherapy response:
Selected Publications
Oncology models generated by ingenious targeting laboratory:
Mlynarczyk C et al. (2023).
BTG1 mutation yields supercompetitive B cells primed for malignant transformation. ↗Science 379(6629): eabj0412
Chakrabarti S et al. (2024).
Touch sensation requires the mechanically gated ion channel ELKIN1. ↗Science 383(6686): 992-998
Clausen BE et al. (1999).
Conditional gene targeting in macrophages and granulocytes using LysMcre mice. ↗Transgenic Research 8(4): 265-277
What Researchers Say
“I'd like to thank the ingenious team for making this mouse for us. We are so excited! Everyone at ingenious has been wonderful to work with throughout the entire process. We will definitely be in contact the next time we need a mouse!”
— Julia Maxson, PhD
Knight Cancer Institute, Oregon Health & Science University
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