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

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).

In vivo Pooled Screening: A Scalable Tool to Study the Complexity of Aging and Age-Related Disease

“…Similarly, some screens have combined mice engineered to express Cas9 with guide delivery via AAV ( Chow et al, 2017 ) or lentivirus ( Wertz et al, 2020 ; Keys and Knouse 2021 ). Cas9 effector-expressing mice are much more versatile than genetically engineered models, because a single mouse line can be combined with different gRNA libraries to perform a variety of screens ( Lima and Maddalo 2021 ). But some features of aging and age-related disease are more accurately modeled in non-mouse models ( Chu, Szczodry, and Bruno 2010 ; Getz and Reardon 2012 ; Calado and Dumitriu 2013 ; Basil and Morrisey 2020 ; Hoffman et al, 2018 ; Chiou et al, 2020 ).…”

In Vivo Modeling of Tumor Heterogeneity for Immuno‐Oncology Studies: Failures, Improvements, and Hopes

“…Somatically engineered mouse models (SEMMs) inherently achieve these goals. The SEMM is a new category of autochthonous murine tumor modeling where a specific oncogenic signature is directly introduced into somatic cells of a specific organ (Lima & Maddalo, 2021). Methods for tissue‐specific delivery (e.g., intraductal injection for mammary tumors or intratracheal delivery for lung tumors) of viruses or naked DNA are used for genome editing to induce tumorigenesis in the target organ.…”

Drug Discovery Oncology in a Mouse: concepts, Models and Limitations

“…Generation of somatically engineered mouse models (SEMMs) by direct genome editing of somatic cells has several advantages [ 74 ]. First of all, as no embryonic stem cell (ESC) engineering is required, timelines are often reduced, as well as the cost for the generation of each model.…”