A research team has designed a rapid method to genetically alter laboratory mice and then used this method to produce personalized animal models of pediatric glioma, an aggressive type of malignant brain cancer in children.
The new method overcomes several drawbacks in current techniques. The goal is to make it easier for laboratories to achieve precise, reliable results when modifying mice for research studies, especially those involving cancers driven by multiple genetic variations. The method also can be used to modify patient-derived cells to study diseases in a culture dish.
In an article published in the journal Cell, the scientists described their technique, called mosaic analysis with dual recombinase-mediated cassette exchange, or MADR.
"We imagine our method as a continually evolving platform," said the corresponding and senior author. "We hope to keep incorporating new methods to create a type of Swiss army knife for tumor modeling, adaptable to many types of tissues."
The MADR method involves inserting a single copy of genetic material into a specific point on a chromosome in the cell of a mouse embryo or newborn mouse. Each genetic alteration, or mutation, can cause a protein to either stop functioning or acquire a new, abnormal function. Using MADR, scientists were able to introduce both types of mutations into the same mouse.
The mutations reproduced the complex gene expression patterns and pathology found in the pediatric glioma tumors of patients who provided the genetic material. Further, MADR was able to accurately model another aggressive type of pediatric brain tumor-ependymoma-using multi-gene fusions that produced cancer-causing fusion proteins. Importantly, the method precisely targeted the correct tissues, leaving other tissues unaltered, the senior author said.
Currently, scientists modify mice for research in several ways, which can include transplanting cells, using deactivated viruses to ferry genetic material into cells or breeding genetically engineered animals. These techniques can present incomplete pictures of tumors, entail biohazard risk, be costly and time-consuming, or cause unintended cancers in other tissues, the senior author said. MADR is designed to overcome some of these problems.
Another author explained that better mouse models are critical to understanding diseases such as pediatric glioma, in which a single tumor may contain many different clones, each with its own combination of gene mutations and altered biochemical pathways. This complexity helps the tumor evolve to resist treatments..
The study demonstrated that MADR successfully altered not only mouse cells but also human cells that had been modified to include an appropriate recipient site. "This finding shows the potential for scientists to incorporate MADR into 'disease in a dish' studies involving a wide range of disorders," the co-author said.
New technology to genetically modify lab mice and human cells
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