Science: Using CRISPR to build a melanoma model from scratch

Over the past 20 years, researchers have discovered genetic mutations in thousands of cancers, but understanding how they affect tumor growth and spread in the body remains a challenge because each patient's tumor can have many different mutations

Now, scientists at the Broad Institute of MIT and Harvard have used the CRISPR-Cas9 gene-editing system to create a cellular model of the deadliest skin cancer, melanoma

Because the researchers introduced mutations one at a time in a controlled manner, they were able to pinpoint the impact of individual and specific combinations of mutations

The work is the first time scientists have used precisely controlled genetic engineering to create a human cancer model from fully differentiated or specialized cells, rather than stem cells, said Eran Hodis, first author and one of the corresponding authors of the study

"With this toolbox, we can ask what effect the mutation has on the cell," said Elena Torlai Triglia, a postdoctoral scholar at Broad University and one of the first authors

"To design these models, we had to combine cutting-edge, precise gene editing techniques with high-resolution, massively parallel single-cell genomics analysis to generate and characterize cells and tumors, and machine learning algorithms to analyze the data

make melanoma

When studying melanoma, it is especially difficult to correlate the genetic makeup or genotype of the tumor with specific characteristics or phenotypes

To make their melanoma model, the team used CRISPR-Cas9 to install mutations in the CDKN2A, BRAF and TERT genes commonly found in melanoma

Next, the researchers added different combinations of additional mutations to the known melanoma genes PTEN, TP53 and APC, creating nine different cell models, which were then implanted in mice

Melanoma is notorious for early metastases -- an often fatal process whose genetic basis is unknown

Hodis, Torlai Triglia and Regev plan to use their method to create more cancer models and study mutations that are not yet known