Abstract 67: Establishment and in-depth characterization of a genetically engineered mouse model of metastatic colorectal cancer

Abstract

Abstract Background: Most novel antitumor compounds fail in the clinic despite promising efficacy in preclinical mouse experiments. This indicates a lack of good mouse models and an apparent discrepancy in the treatability of murine and human tumors. Genetically engineered mouse models (GEMM) may overcome these limitations as they show clinically realistic responses to most standard therapies. A recently published GEMM of colorectal cancer showed reproducible induction of colorectal adenoma and carcinoma (CRC) formation, but developed distant metastasis in only a small fraction of mice. As in CRC it is the distant metastasis rather than the primary tumor which determines the outcome, we aimed to develop a model with higher incidence of hepatic metastases from genetically induced CRC. Materials/Methods: We crossed mice with conditional (“floxed”) alleles of Apc loss, Kras G12D, Tp53 loss or Tp53 R172H and induced tumorigenesis by segmental infection of the colon with cre adenovirus. Additionally, a GFP reporter allele was introduced, allowing non-invasive imaging of the tumors and their metastases. Tumor formation was monitored via colonoscopy. Serum tumor marker levels were quantified and the survival of the animals was monitored. Histology was performed at predefined time points. Selected tumors were analysed by next-generation exome sequencing. Results: Tumor formation was observed in >90% of infected animals. Biallelic loss of Apc resulted in adenoma formation, which over time developed into invasive carcinoma. Loss of Apc in combination with an activing Kras mutation resulted in primary carcinoma formation. Additional biallelic loss of Tp53 resulted in fast-growing, but non-metastatic CRC formation. Mice with an R172H point mutation in Tp53 developed distant metastases in liver and lungs at ∼30%, which corresponds well to clinical data of CRC patients. Survival of mice with loss or mutation of Tp53 was significantly shorter compared to mice with wild-type Tp53. Histologic analyses showed classical adenocarcinomas of the colon closely mimicking human tumors. Monitoring of serum tumor markers and fluorescence imaging allow non-invasive monitoring of tumor growth and overall tumor burden. Exome sequencing of the tumors revealed a genetic progression of the disease with accumulation of new mutations over time. Conclusion: We have established and characterized a clinically highly relevant novel mouse model of colorectal cancer, allowing both basic science as well as therapeutic studies with clinically relevant end-points such as survival and distant metastasis. Citation Format: Sebastian Schölch, Linda Blickensdörfer, Wilko Weichert, Michael Muders, Jürgen Weitz, Moritz Koch. Establishment and in-depth characterization of a genetically engineered mouse model of metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2014-67