Abstract
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).
Highlights
Integrative molecular analysis of human and cancer genomes has thrown a spotlight on the immense complexity of tumor biology [1]
Engineered Mouse Models (GEMMs) of cancer can be invaluable in defining mechanisms driving tumor initiation, progression, and response to therapy [4]
Despite the wealth of information, they could provide a few challenges that have so far limited the use of Genetically Engineered Mouse Models (GEMMs) for preclinical drug development
Summary
Integrative molecular analysis of human and cancer genomes has thrown a spotlight on the immense complexity of tumor biology [1]. The generation of GEMMs is timeconsuming because it requires several steps such as precise gene targeting in Embryonic Stem Cells (ESCs), implantation, germline transmission, and colony expansion before achieving an experimental cohort. Timelines of this process would be further expanded when multiple allele engineering is required. The ideal GEMM would develop tumors in a specific tissue as a consequence of mutations occurring in somatic cells rather than the germline Even if this last point has been partially addressed by generating conditional models leveraging the Crerecombinase or Tet-on inducible systems, the amount of breeding and crossing required makes the process tedious and expensive. SEMMs offer the unique advantage of screening directly in vivo for genes contributing to tumor development, and resistance in a specific organ of interest
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