by akronbiotech

Organoids enable the the long-term in vitro expansion of epithelial tissues, starting from a single adult stem cell. In a new study, organoid technology was combined with CRISPR gene editing to study mutational signatures in cancer. One of the big challenges of studying mutations in cancers is the lack of engineered systems that can be used the recapitulate these mutations and then match them to real case data. Now, a study from the lab of Dr. Hans Clevers at the University Medical Center in Utrech, Netherlands, demonstrated a hybrid approach that can achieve better analysis of cancer-inducing mutations.

By combining the ability to modify organoids using Crispr-Cas9 with a systematic model to examine DNA repair deficiency, the authors established specific DNA mutational signals which lead to cancer.

To do so, the authors introduced loss-of-function mutations in the MMR gene MutL homolog 1 (MLH1). These mutations predispose people to colorectal cancer.

The authors used organoids derived from human normal colon epithelium, being the closest to colorectal cancer cells-of-origin. By inducing mutations in key DNA repair genes, they induced a model whereby



Figure 1. Signatures of mutational processes in DNA repair–deficient organoids. From Drost et al. 2017. Copyright Science Magazine/AAAS.


Following engineered knockout MLH1 organoids validation, the authors constructed NTHL1 knockout organoids, and  demonstrated that a high contribution of signature 30 mutations within a tumor can be indicative of cancer-predisposing germline mutations in the base excision repair gene NTHL1.

The study is interesting because, despite it being a proof-of-concept, it illustrates the ability to use organoids as not only complex tissue mimics, but also carriers of functionally important genomic information.

The study, titled Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer, was published in Science and can be accessed here.


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