Illuminating Cancer Systems with Genetically Engineered Mouse Models and Coupled Luciferase Reporters In Vivo

Schematic representation demonstrating the fabrication and in vivo evaluation of an immune-modulatory nano-formulation consisting of irinotecan and curcumin in immune-competent mouse models of pancreatic adenocarcinoma.

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How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

Journal of Clinical Oncology ◽

10.1200/jco.2010.30.8304 ◽

2011 ◽

Vol 29 (16) ◽

pp. 2273-2281 ◽

Cited By ~ 72

Author(s):

Katerina Politi ◽

William Pao

Keyword(s):

Mouse Models ◽

Cancer Biology ◽

Human Cancer ◽

Genetically Engineered ◽

Mouse Tumor ◽

Tumor Models ◽

Genetically Engineered Mouse Models ◽

Human Cancers ◽

Chemically Induced

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review.

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Genetically Engineered Mouse Models of Liver Tumorigenesis Reveal a Wide Histological Spectrum of Neoplastic and Non-Neoplastic Liver Lesions

Cancers ◽

10.3390/cancers12082265 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2265

Author(s):

Katja Steiger ◽

Nina Gross ◽

Sebastian A. Widholz ◽

Roland Rad ◽

Wilko Weichert ◽

...

Keyword(s):

Mouse Models ◽

Liver Tumors ◽

Genetically Engineered ◽

Liver Lesions ◽

Genetically Engineered Mouse Models ◽

Chemically Induced ◽

Wide Range ◽

Correct Application ◽

Huge Variety

Genetically engineered mouse models (GEMM) are an elegant tool to study liver carcinogenesis in vivo. Newly designed mouse models need detailed (histopathological) phenotyping when described for the first time to avoid misinterpretation and misconclusions. Many chemically induced models for hepatocarcinogenesis comprise a huge variety of histologically benign and malignant neoplastic, as well as non-neoplastic, lesions. Such comprehensive categorization data for GEMM are still missing. In this study, 874 microscopically categorized liver lesions from 369 macroscopically detected liver “tumors” from five different GEMM for liver tumorigenesis were included. The histologic spectrum of diagnosis included a wide range of both benign and malignant neoplastic (approx. 82%) and non-neoplastic (approx. 18%) lesions including hyperplasia, reactive bile duct changes or oval cell proliferations with huge variations among the various models and genetic backgrounds. Our study therefore critically demonstrates that models of liver tumorigenesis can harbor a huge variety of histopathologically distinct diagnosis and, depending on the genotype, notable variations are expectable. These findings are extremely important to warrant the correct application of GEMM in liver cancer research and clearly emphasize the role of basic histopathology as still being a crucial tool in modern biomedical research.

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A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPRCas9 mediated somatic recombination

10.1101/398347 ◽

2018 ◽

Author(s):

Noboru Ideno ◽

Hiroshi Yamaguchi ◽

Takashi Okumara ◽

Jonathon Huang ◽

Mitchel J. Brun ◽

...

Keyword(s):

Mouse Models ◽

Mouse Strain ◽

Gene Editing ◽

High Efficiency ◽

Intraepithelial Neoplasia ◽

Genetically Engineered ◽

Ductal Adenocarcinoma ◽

Specific Expression ◽

Genetically Engineered Mouse Models

ABSTRACTGenetically engineered mouse models (GEMMs) that recapitulate the major genetic drivers in pancreatic ductal adenocarcinoma (PDAC) have provided unprecedented insights into the pathogenesis of this lethal neoplasm. Nonetheless, generating an autochthonous model is an expensive, time consuming and labor intensive process, particularly when tissue specific expression or deletion of compound alleles are involved. In addition, many of the current PDAC GEMMs cause embryonic, pancreas-wide activation or loss of driver alleles, neither of which reflects the cognate human disease scenario. The advent of CRISPR/Cas9 based gene editing can potentially circumvent many of the aforementioned shortcomings of conventional breeding schema, but ensuring the efficiency of gene editing in vivo remains a challenge. Here we have developed a pipeline for generating PDAC GEMMs of complex genotypes with high efficiency using a single “workhorse” mouse strain expressing Cas9 in the adult pancreas under a p48 promoter. Using adeno-associated virus (AAV) mediated delivery of multiplexed guide RNAs (sgRNAs) to the adult murine pancreas of p48-Cre; LSL-Cas9 mice, we confirm our ability to express an oncogenic KrasG12D allele through homology-directed repair (HDR), in conjunction with CRISPR-induced disruption of cooperating alleles (Trp53, Lkb1 and Arid1A). The resulting GEMMs demonstrate a spectrum of precursor lesions (pancreatic intraepithelial neoplasia [PanIN] or Intraductal papillary mucinous neoplasm [IPMN] with eventual progression to PDAC. Next generation sequencing of the resulting murine PDAC confirms HDR of oncogenic KrasG12D allele at the endogenous locus, and insertion deletion (“indel”) and frameshift mutations of targeted tumor suppressor alleles. By using a single “workhorse” mouse strain and optimal AAV serotype for in vivo gene editing with combination of driver alleles, we have created a facile autochthonous platform for interrogation of the PDAC genome.

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Deciphering the RAS/ERK pathway in vivo

Biochemical Society Transactions ◽

10.1042/bst20160135 ◽

2017 ◽

Vol 45 (1) ◽

pp. 27-36 ◽

Cited By ~ 21

Author(s):

Coralie Dorard ◽

Georg Vucak ◽

Manuela Baccarini

Keyword(s):

Mouse Models ◽

Short Review ◽

Genetically Engineered ◽

Tissue Homeostasis ◽

Pharmacological Intervention ◽

Erk Pathway ◽

Erk Activation ◽

Genetically Engineered Mouse Models ◽

Mutational Activation

The RAS/ERK pathway has been intensely studied for about three decades, not least because of its role in human pathologies. ERK activation is observed in the majority of human cancers; in about one-third of them, it is driven by mutational activation of pathway components. The pathway is arguably one of the best targets for molecule-based pharmacological intervention, and several small-molecule inhibitors are in clinical use. Genetically engineered mouse models have greatly contributed to our understanding of signaling pathways in development, tissue homeostasis, and disease. In the specific case of the RAS/ERK pathway, they have revealed unique biological roles of structurally and functionally similar proteins, new kinase-independent effectors, and unsuspected relationships with other cascades. This short review summarizes the contribution of mouse models to our current understanding of the pathway.

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A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPR-Cas9-mediated somatic recombination

Laboratory Investigation ◽

10.1038/s41374-018-0171-z ◽

2019 ◽

Vol 99 (8) ◽

pp. 1233-1244 ◽

Cited By ~ 10

Author(s):

Noboru Ideno ◽

Hiroshi Yamaguchi ◽

Takashi Okumura ◽

Jonathon Huang ◽

Mitchell J. Brun ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Models ◽

Genetically Engineered ◽

Genetically Engineered Mouse Models ◽

Somatic Recombination

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In vivo models of brain tumors: roles of genetically engineered mouse models in understanding tumor biology and use in preclinical studies

Cellular and Molecular Life Sciences ◽

10.1007/s00018-014-1675-3 ◽

2014 ◽

Vol 71 (20) ◽

pp. 4007-4026 ◽

Cited By ~ 22

Author(s):

Iva Simeonova ◽

Emmanuelle Huillard

Keyword(s):

Brain Tumors ◽

Mouse Models ◽

Tumor Biology ◽

Genetically Engineered ◽

Preclinical Studies ◽

In Vivo Models ◽

Genetically Engineered Mouse Models

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SEMMs: Somatically Engineered Mouse Models. A New Tool for In Vivo Disease Modeling for Basic and Translational Research

Frontiers in Oncology ◽

10.3389/fonc.2021.667189 ◽

2021 ◽

Vol 11 ◽

Author(s):

Anthony Lima ◽

Danilo Maddalo

Keyword(s):

Mouse Models ◽

Disease Modeling ◽

Genetically Engineered ◽

Response To Therapy ◽

Preclinical Models ◽

Screening Programs ◽

Genetically Engineered Mouse Models ◽

Direct Mutation ◽

Xenograft Models

Most experimental oncology therapies fail during clinical development despite years of preclinical testing rationalizing their use. This begs the question of whether the current preclinical models used for evaluating oncology therapies adequately capture patient heterogeneity and response to therapy. Most of the preclinical work is based on xenograft models where tumor mis-location and the lack of the immune system represent a major limitation for the translatability of many observations from preclinical models to patients. Genetically engineered mouse models (GEMMs) hold great potential to recapitulate more accurately disease models but their cost and complexity have stymied their widespread adoption in discovery, early or late drug screening programs. Recent advancements in genome editing technology made possible by the discovery and development of the CRISPR/Cas9 system has opened the opportunity of generating disease-relevant animal models by direct mutation of somatic cell genomes in an organ or tissue compartment of interest. The advent of CRISPR/Cas9 has not only aided in the production of conventional GEMMs but has also enabled the bypassing of the construction of these costly strains. In this review, we describe the Somatically Engineered Mouse Models (SEMMs) as a new category of models where a specific oncogenic signature is introduced in somatic cells of an intended organ in a post-natal animal. In addition, SEMMs represent a novel platform to perform in vivo functional genomics studies, here defined as DIVoS (Direct In Vivo Screening).

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