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Review
. 2024 Apr 24;52(2):803-819.
doi: 10.1042/BST20230984.

Deconstructing cancer with precision genome editing

Grace A Johnson #  1   2 , Samuel I Gould #  1   2 , Francisco J Sánchez-Rivera  1   2
Affiliations
Review

Deconstructing cancer with precision genome editing

Grace A Johnson et al. Biochem Soc Trans. .

Abstract

Recent advances in genome editing technologies are allowing investigators to engineer and study cancer-associated mutations in their endogenous genetic contexts with high precision and efficiency. Of these, base editing and prime editing are quickly becoming gold-standards in the field due to their versatility and scalability. Here, we review the merits and limitations of these precision genome editing technologies, their application to modern cancer research, and speculate how these could be integrated to address future directions in the field.

Keywords: CRISPR; functional genomics; genetics; genome editing; genomics; mouse models.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. The modular precision genome editing toolkit.
(A) Traditional CRISPR-Cas9 systems generated double stranded breaks (DSBs) after being directed to a locus by a sgRNA. This DSB can be resolved via non-homologous end joining (NHEJ), or via homology directed repair (HDR) when provided with an exogenous donor DNA template. (B) Different precision genome editors are generated by fusing effector domains to different Cas proteins. These editors take direction from the information encoded within sgRNAs or pegRNAs.
Figure 2.
Figure 2.. Applications of precision genome editing to interrogate cancer-associated phenotypes.
(A) In cell-based systems and animal models, single or multiplexed guides can be delivered to editor-expressing cells to generate cells harboring endogenous genetic variants. These variant-harboring cells can then be tested for various phenotypes. (B) Schematic of precision genome editing screens. After cells are edited to harbor the desired set of endogenous variants, selective pressures or perturbations, including drugs, co-culture assays, nutrient availability, and in vivo tumor microenvironments, can be applied to this cell population. Subsequently, cell phenotypes can be read out via e.g. next generation sequencing (NGS) to count the relative abundance of variant-harboring cells, different ‘omics’ approaches, or optical screening. Analysis of these phenotypic readouts can be used to gain biological insight into variant functions.
Figure 3.
Figure 3.. Dissecting the hallmarks of cancer with precision genome editing.
Precision genome editing has been used to interrogate a subset of the hallmarks of cancer (labeled as ‘tested’ in white). References for papers that have evaluated these hallmarks are listed with reference numbers. Developments in the field will empower future studies to dissect all of the hallmarks of cancer. Adapted from Hanahan and Weinberg [3].
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