Cancer cells growing in a dish
Scientists have mapped out the genes that keep our cells alive, creating a long-awaited foothold for understanding how our genome works and which genes are crucial in disease like cancer. A team of Toronto researchers have switched off, one by one, almost 18,000 genes – 90% of the entire human genome – to find the genes that are essential for cell survival. The data revealed a “core” set of more than 1,500 essential genes. This lays the foundation for reaching the long-standing goal in biomedical research of pinpointing a role for every single gene in the genome.
By turning genes off in 5 different cancer cell lines, including brain, retinal, ovarian, and 2 kinds of colorectal cancer cells, the team uncovered that each tumour relies on a unique set of genes that can be targeted by specific drugs. The finding raises hope of devising new treatments that would target only cancer cells, leaving the surrounding healthy tissue unharmed. “It’s when you get outside the core set of essential genes, that it starts to get interesting in terms of how to target particular genes in different cancers and other disease states,” says Prof. Moffat.
Sequencing of the human genome 12 years ago allowed scientists to compile a list of parts – our 20,000 genes – that make up our cells and bodies. But we still didn’t understand the function of each gene, or how some genes make us sick when they go wrong. To do this, scientists would have to switch genes off, one by one to determine what processes go wrong in the cells. But the available tools were inaccurate or too slow.
Highlights •Identification of 5-fold more fitness genes in human cells than previously observed •Core fitness genes are highly enriched for ancient protein complexes •Context-specific fitness genes illuminate biological differences between cell types •Distinct genetic signatures can be used to predict differential drug response
The recent arrival of the gene editing technology CRISPR has finally made it possible to turn genes off, swiftly and with pinpoint accuracy. ~10% of our genes were found to be essential for cell survival. The majority of human genes play more subtle roles in the cell because switching them off doesn’t kill the cell. But if 2 or more of such genes are mutated at the same time, or cells are under environmental stress, their loss begins to count. As different cancers have different mutations, they tend to rely on different sets of genes to survive. Moffatt’s team have identified distinct sets of “smoking gun” genes for each of the tested cancers – each set susceptible to different drugs.
In his study, metformin, a widely prescribed diabetes drugs successfully killed brain cancer cells and those of one form of colorectal cancer – but was useless against the other cancers he studied. However, the antibiotics chloramphenicol and linezolid were effective against another form of colorectal cancer, and not against brain or other cancers studied. These data illustrate the clinical potential of the data in pointing to more precise treatments for the different cancers – and show the value of personalized medicine.
“The Moffat group has developed a powerful CRISPR library that could be used by investigators around the world to identify new treatment strategies for the treatment of cancer,” says Prof A Schimme. ” I would be interested in using this tool to identify new treatment approaches for acute myeloid leukemia – a blood cancer with a high mortality rate.” http://tdccbr.med.utoronto.ca/news/new-gene-map-reveals-cancer%E2%80%99s-achilles-heel http://www.cell.com/cell/abstract/S0092-8674(15)01495-6
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