summary: A new method has been developed using the CRISPR-Cas9 gene-editing tool to model liver cancer tumor subtypes that are caused by mutations in the same genes. By targeting one section of the mouse gene, Ctnnb1, the researchers were able to generate two distinct tumor subtypes, which enhance the activity of the protein to promote tumor growth, which may allow the development of new therapeutic interventions in the future.
Mutations in our genes can lead to serious problems, such as colon or liver cancer. But cancer is very complex. Mutations in the same genes can lead to different subtypes of tumors in different people. Currently, scientists do not have a good way to produce such subtypes of tumors for study in the laboratory.
Now, Cold Spring Harbor Laboratory Associate Professor Professor Samir Beyaz has devised a new method for modeling specific subtypes of liver cancer tumors using the gene-editing tool CRISPR-Cas9.
Genes contain the information our bodies need to produce proteins. Very similar proteins produced from the same gene are called isoforms. Different isoforms generate different tumors. This process is known as exon skipping, in which multiple parts of a gene are put together to make a different version of the protein.
“Everyone thinks cancer is only one type,” Beaz explains. “But with different isoforms, you can end up with subtypes of cancer that have different characteristics.”
Bayaz and colleagues generated two distinct tumor subtypes by targeting one part of a mouse gene, ctnnb1, with CRISPR. The tool is mostly used to inhibit gene function. This is the first time that CRISPR technology has been used to generate different cancer-causing gain-of-function mutants in mice.
These mutations enhance the activity of the protein to promote tumor growth. The team ranked each tumor subtype to see which isoform was associated with the differences they observed.
“We were able to identify those isoforms that are associated with different subtypes of cancer,” says Bayaz. “This was, for us, a surprising discovery.”
Next, to confirm that these are actually isoforms it causes Variations, they produced it in the mouse without using CRISPR. They found that they were indeed able to generate two different tumor subtypes with their respective characteristics. Both liver tumor subtypes are also found in humans.
Mutations targeted by albino can lead to colon and liver cancer. Targeting exon skipping has emerged as a potential therapeutic approach for treating cancer and other diseases. Beyaz’s new study method allows the researchers to investigate this phenomenon in live mouse cells using CRISPR. The platform could one day help researchers develop new treatment interventions.
“Ultimately, what we want to do is find the best models to study the biology of cancer so that we can find a cure,” Bayez explains.
Written summary with help ChatGPT AI technology
About this cancer research news and genetics
author: Samuel Diamond
communication: Samuel Diamond – CSHL
picture: Image credits Beyaz Laboratory/Cold Spring Harbor Laboratory
Original search: open access.
“CRISPR-induced exon skipping of β-catenin reveals oncogenic mutations that lead to distinct subtypes of liver cancer” by Semir Beyaz et al. Pathology Journal
CRISPR-induced exon skipping of β-catenin reveals oncogenic mutations that lead to distinct subtypes of HCC
CRISPR/Cas9-based cancer modeling studies are based on inactivation of tumor suppressor genes by small insertions or deletions (indels) that lead to frameshift mutations.
In addition, CRISPR/Cas9 is widely used to determine the significance of cancer genes and genetic dependence in loss-of-function studies. However, how CRISPR/Cas9 affects oncogenic gain-of-function mutations is elusive.
Here, we show that single guide RNA targets exon 3 of a RNA ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms He lives. CRISPR/Cas9-mediated exon skipping ctnnb1 It induces liver tumor formation synergistically with YAPS127A in mice. We identify two distinct subtypes of tumors caused by exon skipping with different histological and transcriptional features.
Remarkably, ectopic expression of two isoforms of β-catenin transcriptome coexpressed with YAPS127A Phenocopies are two distinct subtypes of hepatocellular carcinoma. Further, we define the like CTNNB1 Exon skipping events in hepatocellular carcinoma patients. c
Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be redirected, He livesTo study gain-of-function mutations of oncogenes in cancer.