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Luciferase Expressing Preclinical Model Systems Representing the Different Molecular Subtypes of Colorectal Cancer
Arne Rotermund1, Martin S Staege2, Sarah Brandt1
1Department of Internal Medicine IV, Hematology and Oncology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
Cancers
|August 26, 2023
Summary
This study developed advanced colorectal cancer (CRC) models, including 3D spheroids and xenografts, to better understand CRC heterogeneity and test therapies. These models accurately reflect patient tumors and reveal potential resistance markers like CAV1 to oxaliplatin treatment.
Area of Science:
- Oncology
- Cancer Biology
- Preclinical Research
Background:
- Colorectal cancer (CRC) is a complex disease with significant biological diversity.
- Understanding CRC heterogeneity is crucial for improving patient treatment outcomes.
- Established cell lines serve as valuable models for CRC subtypes at genomic and transcriptomic levels.
Purpose of the Study:
- To establish and characterize novel preclinical models of colorectal cancer (CRC) that reflect its heterogeneity.
- To compare the biological characteristics of 2D cell cultures, 3D spheroids, and in vivo xenografts.
- To evaluate the efficacy of oxaliplatin treatment in these advanced CRC models and identify potential resistance markers.
Main Methods:
- Generation of 10 stable, luciferase-expressing CRC cell line derivatives.
- Creation of 3D spheroids and subcutaneous xenograft tumors in nude mice.
- Transcriptomic analysis, CMS classification, and bioluminescence imaging for comparative characterization.
- Development of a bioluminescence-based spheroid cytotoxicity assay for drug response studies.
Main Results:
- Transcriptomic data confirmed the close relationship between cell lines, spheroids, and xenografts, mirroring patient tumor characteristics.
- 3D spheroids more closely resembled xenografts than 2D cultures in representing primary tumor features.
- A significant reduction in oxaliplatin response was observed in 7/10 cell lines using the 3D spheroid model compared to 2D.
- CAV1 was identified as a potential biomarker for oxaliplatin resistance.
Conclusions:
- A comprehensive 2D/3D, in vitro/in vivo preclinical model system for colorectal cancer (CRC) was successfully established.
- These models effectively represent CRC heterogeneity and can be utilized for preclinical research and drug development.
- The findings highlight the utility of 3D models for predicting drug response and identifying resistance mechanisms in CRC.
