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Applications of the CRISPR–Cas9 system in cancer biology

Nature Reviews Cancer volume 15, pages 387–393 (2015)Cite this article

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Abstract

The prokaryotic type II CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated 9) system is rapidly revolutionizing the field of genetic engineering, allowing researchers to alter the genomes of a large range of organisms with relative ease. Experimental approaches based on this versatile technology have the potential to transform the field of cancer genetics. Here, we review current approaches for functional studies of cancer genes that are based on CRISPR–Cas, with emphasis on their applicability for the development of next-generation models of human cancer.

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Figure 1: Genome engineering using the CRISPR–Cas9 system.
Figure 2: Potential applications of the CRISPR–Cas9 system in cancer biology.
Figure 3: Applications of the CRISPR–Cas9 system in cancer biology.

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Acknowledgements

Work in the Jacks laboratory is supported by the Howard Hughes Medical Institute, the National Cancer Institute (US National Institutes of Health), the Ludwig Fund for Cancer Research, the Lustgarten Foundation and the US Department of Defense. T.J. is a Daniel K. Ludwig Scholar and the David H. Koch Professor of Biology at Massachusetts Institute of Technology.

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Authors and Affiliations

  1. David H. Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Francisco J. Sánchez-Rivera & Tyler Jacks

  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Tyler Jacks

Authors
  1. Francisco J. Sánchez-Rivera
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Correspondence to Tyler Jacks.

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PowerPoint slides

Glossary

Allografts

Tumour tissues or cell lines from one species that have been implanted into a recipient of the same species.

Cancer genes

Genes that have a causal role in carcinogenesis, such as tumour-promoting genes (commonly referred to as 'oncogenes') and tumour-suppressor genes.

Chimeric antigen receptor-modified T cells

(CAR T cells). T cells that have been modified to express a synthetically engineered T cell receptor composed of a single-chain antibody, that allows for tumour recognition, fused with additional intracellular signalling domains derived from the T cell receptor and other co-stimulatory molecules.

Conditional alleles

Engineered alleles, the expression of which is strictly dependent on the presence of a second component, such as Cre recombinase for loxP-based conditional alleles.

CRISPR RNA

(crRNA). In natural CRISPR (clustered regularly interspaced short palindromic repeats) systems, CRISPR loci contain crRNAs that are composed of a repeat portion and a variable portion, the latter corresponding to invader-specific DNA sequences that form the basis of this prokaryotic adaptive immune system.

Genetically engineered mouse models

(GEMMs). Mice genetically engineered to express either exogenous or endogenous mutated genes. For GEMMs of cancer, the modified genes are usually cancer genes.

Haploinsufficient

A genetic state in which the presence of a single functional copy of a gene (as a result of mutation or loss of the other functional copy of the gene) produces a mutant phenotype.

Homology-directed repair

(HDR). A precise DNA repair pathway in which the cell uses the homologous chromosome or sister chromatid (or an exogenous donor DNA molecule provided by the investigator) as a template for repairing a double-strand break. Homologous recombination is a form of HDR.

'Hotspot' regions

Specific regions of a gene in which mutations are observed with greater frequency.

Hydrodynamic gene transfer

A technique that allows for delivery of DNA via the application of hydrodynamic pressure in capillaries, which greatly enhances endothelial and parenchymal cell permeability, leading to efficient transfer of DNA.

Indels

Mutations that arise because of small insertions or deletions of DNA sequences.

Non-homologous end joining pathway

(NHEJ pathway). An error-prone cellular DNA repair pathway that involves the modification and subsequent ligation of two broken DNA ends generated by a double-strand break. This pathway can result in insertion or deletion mutations due to the addition or removal of nucleotides at the break before ligation.

Organoid cultures

A type of in vitro culture in which stem cells or organ progenitors are embedded in a three-dimensional matrix in which they self-assemble into epithelia that very closely resemble the organ of origin. These organoid cultures offer several advantages over traditional cell culture, the main one being that they very closely recapitulate the physiology of the native epithelial organ of origin.

Patient-derived xenografts

A type of xenograft in which fresh tumour tissue obtained from a cancer patient is implanted directly into an immunodeficient mouse.

Protospacer adjacent motif

(PAM). A nucleotide sequence immediately adjacent to the target sequence that is critically required for CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas)-mediated recognition and cleavage. In natural CRISPR systems, the PAM sequence allows for self versus non-self discrimination by virtue of the absence of PAM sequences in endogenous CRISPR loci.

Single guide RNA

(sgRNA). A chimeric RNA molecule generated by the fusion of a CRISPR (clustered regularly interspaced short palindromic repeats) RNA (crRNA) and a trans-activating crRNA (tracrRNA) that guides Cas9 (CRISPR-associated 9) to a specific genomic target via a unique guide RNA sequence present in the 5′ region of the crRNA.

Site-specific recombinases

Enzymes (for example, Cre and flippase (Flp)) that can catalyse the recombination between specific pairs of inverted repeat sequences (for example, loxP sequences for Cre and Flp recombination target (FRT) sequences for Flp).

Trans-activating crRNA

(tracrRNA). In natural CRISPR (clustered regularly interspaced short palindromic repeats) systems, the tracrRNA is a trans-encoded RNA molecule that is critical for the processing of pre-CRISPR RNA (pre-crRNA) loci into mature crRNAs.

Transcription activator-like effector nucleases

(TALENs). Site-specific DNA endonucleases that are composed of specific DNA-binding domains from TALE proteins and the nuclease domain of the FokI restriction enzyme.

Xenografts

Tumour tissues or cell lines from one species that have been implanted into another species. In cancer research, this frequently entails the implantation of material from one species into an ectopic or orthotopic site of an immunodeficient mouse.

Zinc-finger nucleases

(ZFNs). Site-specific DNA endonucleases that are composed of specific DNA-binding domains from zinc-finger proteins and the nuclease domain of the FokI restriction enzyme.

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Sánchez-Rivera, F., Jacks, T. Applications of the CRISPR–Cas9 system in cancer biology. Nat Rev Cancer 15, 387–393 (2015). https://doi.org/10.1038/nrc3950

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