Cold Spring Harbor Laboratory researchers developed a new method to model liver cancer tumor subtypes with CRISPR-Cas9. Currently, scientists do not have an effective way to produce such tumor subtypes, despite knowing that genetic mutations can lead to severe health issues, like colon or liver cancer. This is primarily because mutations in the same genes can result in different tumor subtypes in different people, making it challenging to study in the lab.
The study, led by Assistant Professor Semir Beyaz and published in the Journal of Pathology, produced two distinct tumor subtypes by targeting a single section of the mouse gene, Ctnnb1, with CRISPR. The mutations targeted by the team can lead to colon and liver cancers, and targeting exon skipping has emerged as a potential therapeutic approach for treating cancer and other diseases. The group sequenced each tumor subtype to determine which isoform was associated with the observed differences.
Next, to confirm that these isoforms actually caused these variances, the researchers produced them in mice without using CRISPR. Ultimately, they found that they were indeed able to generate the two different tumor subtypes with their respective characteristics. Both liver tumor subtypes are also observed in humans.
This new method allows researchers to investigate exon skipping in living mice cells using CRISPR, hopefully helping to find a cure for cancer. CRISPR-Cas9-driven cancer modeling studies are based on disruptions of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR-Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive.
The study also revealed that CRISPR-Cas9 could be repurposed in vivo to analyze gain-of-function mutations of oncogenes. This information can advance our understanding of β-catenin-related tumorigenesis and demonstrate that it can be used to refine liver cancer classification. By better understanding β-catenin mutations in liver tumorigenesis, scientists can define disease heterogeneity and patient outcomes, leading to better therapeutic interventions.
Beyaz’s new method of modeling liver cancer tumor subtypes allows researchers to investigate cancer biology in mice cells. By targeting exon skipping and gain-of-function mutations of oncogenes, scientists can refine liver cancer classification and develop better therapeutic interventions.