In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system

By Danilo Maddalo, Eusebio Manchado, Carla P. Concepcion, Ciro Bonetti, Joana A. Vidigal, Yoon-Chi Han, Paul Ogrodowski, A. Crippa, N. Rekhtman, E. de Stanchina and 2 more. Nature, 2014

622 citations recorded by the source corpus.

Chromosomal rearrangements have a central role in the pathogenesis of human cancers and often result in the expression of therapeutically actionable gene fusions. A recently discovered example is a fusion between the genes echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK), generated by an inversion on the short arm of chromosome 2: inv(2)(p21p23). The EML4–ALK oncogene is detected in a subset of human non-small cell lung cancers (NSCLC) and is clinically relevant because it confers sensitivity to ALK inhibitors. Despite their importance, modelling such genetic events in mice has proven challenging and requires complex manipulation of the germ line. Here we describe an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals. We apply it to generate a mouse model of Eml4–Alk-driven lung cancer. The resulting tumours invariably harbour the Eml4–Alk inversion, express the Eml4–Alk fusion gene, display histopathological and molecular features typical of ALK+ human NSCLCs, and respond to treatment with ALK inhibitors. The general strategy described here substantially expands our ability to model human cancers in mice and potentially in other organisms.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/881f71ff1726454ae9298e33d744721e59e3fbe1

How researchers see this paper

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In Cancer Research

1. Ansuman T. Satpathy
2. Howard Y. Chang
3. Pedro J. Batista
4. Ling-Ling Chen

In Molecular Biology

1. Haifeng Wang
2. Marie La Russa
3. Ansuman T. Satpathy
4. Howard Y. Chang
5. Frederic D. Bushman
6. Jerilyn A. Timlin
7. J. Carney
8. J. C. Harper

Citations in the corpus

• CRISPR/Cas9 in Genome Editing and Beyond. (2016, background): “, cancers and heritable genetic disorders) (107, 110, 111).”
• Delivering CRISPR: a review of the challenges and approaches (2018, background): “Maddalo et al. (2014) reported the generation of a model of Eml4-Alk oncogene-driven lung cancer in adult mice by intratracheal instillation of AdV-delivered CRISPR/Cas9.”
• CRISPR-engineered T cells in patients with refractory cancer (2020, methodology): “CRISPR-Cas9 has been used to intentionally create oncogenic chromosomal rearrangements (38).”