Nonviral CRISPR/Cas9 mutagenesis for streamlined generation of mouse lung cancer models
Year: 2024
Type: article
Abstract: Functional analysis in mouse models is necessary to establish the involvement of a set of genetic variations in tumor development. A modeling platform to facilitate and cost-effectively analyze the role of multiple genes in carcinogenesis would be valuable. Here, we present an innovative strategy for lung mutagenesis using CRISPR/Cas9 ribonucleoproteins delivered via cationic polymers. This approach allows the simultaneous inactivation of multiple genes. We validate the effectiveness of this system by targeting a group of tumor suppressor genes, specifically Rb1 , Rbl1 , Pten , and Trp53 , which were chosen for their potential to cause lung tumors, namely small cell lung carcinoma (SCLC). Tumors with histologic and transcriptomic features of human SCLC emerged after intratracheal administration of CRISPR/polymer nanoparticles. These tumors carried loss-of-function mutations in all four tumor suppressor genes at the targeted positions. These findings were reproduced in two different pure genetic backgrounds. We provide a proof of principle for simplified modeling of lung tumorigenesis to facilitate functional testing of potential cancer-related genes.
Institutions: University College Dublin, Centre for Biomedical Network Research on Rare Diseases, Centro de Investigación Biomédica en Red, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, Universidad Carlos III de Madrid, Instituto de Salud Carlos III, Unidades Centrales Científico-Técnicas, Anhui University of Science and Technology, Centro de Investigación Biomédica en Red de Cáncer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Dystrophic Epidermolysis Bullosa Research Association, Comunidad de Madrid, European Commission, Science Foundation Ireland, Fundación Científica Asociación Española Contra el Cáncer, China Scholarship Council, Debra International, Centro de Investigación Biomédica en Red de Cáncer, DEBRA Austria, Instituto de Salud Carlos III, European Regional Development Fund, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas
Awards: A Disruptive, Non?Viral Gene Editing Platform Technology for Treating Genetic Conditions, Modelos múridos de cáncer (de pulmón): nuevas estrategias de edición génica y detección preclínica de biomarcadores en biopsia liquida, Multifunctional single-chain cyclized/knot polymers and their applications for Recessive Dystrophic Epidermolysis Bullosa (RDEB) wound healing, G2397910235, Corrección de mutaciones que causan RDEB y modulación de la hipersensibilidad al dolor y la inflamación mediante la edición de genes in vivo administrada por vectores virales, G5485603675, G6086807747, G6464286393, G7658215705, Nuevos modelos de cáncer de pulmón de uso preclínico: tumores neuroendocrinos de alto grado y carcinoma epidermoide, G8786576139
OpenAlex ID: W4400280545