Rapid analysis of genes mutated in tumors enabled

Sequencing the genomes of tumor cells has revealed thousands of genetic mutations linked with cancer. However, sifting through this deluge of information to figure out which of these mutations actually drive cancer growth has proven to be a tedious, time-consuming process.

Massachusetts Institute of Technology researchers in Boston have developed a new way to model the effects of these genetic mutations in mice. Their approach, based on the genome-editing technique known as CRISPR, is much faster than existing strategies, which require genetically engineering mice that carry the cancerous mutations.

"It's a very rapid and very adaptable approach to make models," said co-lead author Thales Papagiannakopoulos, PhD, of MIT's Koch Institute for Integrative Cancer Research. "With a lot of these mutations, we have no idea what their role is in tumor progression. If we can actually understand the biology, we can then go in and try targeted therapeutic approaches."

The research team used CRISPR to accurately reproduce the effects of two well-known lung cancer genes. They also modeled the gene APC, whose role in lung cancer was not previously known. Their work was published in Nature (2014; doi:10.1038/nature13589).

This approach could be used to study nearly any gene in many different types of cancer, the researchers said. They explained the need for a functional way to assess the role of the cancer-gene candidates as they appear in sequencing studies. This system fills that gap both rapidly and precisely.

CRISPR, originally discovered by biologists studying the bacterial immune system, involves a set of proteins that bacteria use to defend themselves against bacteriophages (viruses that infect bacteria). One of these proteins, a DNA-cutting enzyme called Cas9, binds to short RNA guide strands that target specific sequences, telling Cas9 where to make its cuts.

Scientists have recently begun exploiting this system to make targeted mutations in the genomes of living animals, either deleting genes or inserting new ones.

To deliver the genes for Cas9 and the RNA guide strand, the MIT team packaged them into viruses called lentiviruses and injected them into the target organs of adult mice. This process is much faster than generating mice with mutations inserted at the embryonic stem cell stage, which can take a year or longer.

In this study, the researchers focused on lung adenocarcinoma, a type of non-small cell lung cancer that accounts for approximately 40% of lung cancers. The research team used mice they had previously engineered that conditionally express the Kras oncogene only in the lung, leading them to develop lung adenocarcinoma.

The researchers administered lentiviruses targeting three different genes into these mice, allowing them to see how each gene cooperates with Kras to influence tumor growth. Once the tumors develop, the researchers can study how aggressive they are, how fast they grow, and how differentiated they are.

"This opens up a whole new field of being able to do personalized oncology where you can model human mutations and start treating tumors based on these mutations," Papagiannakopoulos said.

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