Differential Effects of Trp53 Alterations in Murine Colorectal Cancer
1
Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
2
Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
3
Department of General, Gastrointestinal and Transplant Surgery, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany
4
Institute of Pathology, University of Bonn Medical Center, 53127 Bonn, Germany
5
Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany
6
Institute of Pathology, Technische Universität München, 81675 München, Germany
7
Department of Applied Tumor Biology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany
8
Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
9
Institute of Clinical Genetics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
10
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium
11
Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
12
Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this paper.
‡
Current address: FlowCell Inc., 29 Littles Point Road, Swampscott, MA 01907, USA.
§
Current address: Beilstein-Institut zur Förderung der Chemischen Wissenschaften, 60487 Frankfurt am Main, Germany.
Academic Editor: Masako Nakanishi
Cancers 2021, 13(4), 808; https://doi.org/10.3390/cancers13040808
Received: 18 January 2021
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Revised: 5 February 2021
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Accepted: 8 February 2021
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Published: 15 February 2021
(This article belongs to the Special Issue Preclinical Models of Solid Malignancies)
Simple Summary
Although colorectal cancer is among the most frequent malignant tumors, there are currently no mouse models available that reliably mimic both tumor biology as well as treatment response. In this article, we describe a novel mouse model in which mutations relevant to colorectal cancer are induced in mice, leading to tumor formation in the distal colon. The tumors are monitored via colonoscopy, and the survival and the histology of the tumors are examined. We demonstrate that this model can closely model the human disease clinically, histologically and genetically. In addition, the response of this model to classical colorectal cancer treatments is more realistic than that of other mouse models. The effects of different mutations in the Trp53 gene on tumor cells show striking differences, similar to the effects in other tumor diseases. In summary, the new model allows more accurate and predictive experiments in colorectal cancer.
Background: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. Methods: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. Results: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. Conclusions: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.
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Keywords:
colorectal cancer; genetically engineered mouse model; GEMM; adenovirus; Apc; Kras; Trp53; TP53; metastasis; preclinical studies
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MDPI and ACS Style
Betzler, A.M.; Nanduri, L.K.; Hissa, B.; Blickensdörfer, L.; Muders, M.H.; Roy, J.; Jesinghaus, M.; Steiger, K.; Weichert, W.; Kloor, M.; Klink, B.; Schroeder, M.; Mazzone, M.; Weitz, J.; Reissfelder, C.; Rahbari, N.N.; Schölch, S. Differential Effects of Trp53 Alterations in Murine Colorectal Cancer. Cancers 2021, 13, 808. https://doi.org/10.3390/cancers13040808
AMA Style
Betzler AM, Nanduri LK, Hissa B, Blickensdörfer L, Muders MH, Roy J, Jesinghaus M, Steiger K, Weichert W, Kloor M, Klink B, Schroeder M, Mazzone M, Weitz J, Reissfelder C, Rahbari NN, Schölch S. Differential Effects of Trp53 Alterations in Murine Colorectal Cancer. Cancers. 2021; 13(4):808. https://doi.org/10.3390/cancers13040808
Chicago/Turabian StyleBetzler, Alexander M., Lahiri K. Nanduri, Barbara Hissa, Linda Blickensdörfer, Michael H. Muders, Janine Roy, Moritz Jesinghaus, Katja Steiger, Wilko Weichert, Matthias Kloor, Barbara Klink, Michael Schroeder, Massimiliano Mazzone, Jürgen Weitz, Christoph Reissfelder, Nuh N. Rahbari, and Sebastian Schölch. 2021. "Differential Effects of Trp53 Alterations in Murine Colorectal Cancer" Cancers 13, no. 4: 808. https://doi.org/10.3390/cancers13040808
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