Lung cancer. Image credit: National Cancer Institute via Unsplash (CC0).
How and when cells grow and divide is tightly controlled. Over time, the DNA in cells accumulates changes known as mutations, which sometimes enable cells to ignore control mechanisms and grow into a tumor. While some mutations drive cancer development, most do not and are considered ‘passenger’ mutations. The number of these mutations can vary greatly between different cancers, with some tumors containing only a few while others may have tens of thousands.
There is ongoing debate about whether passenger mutations are neutral or harmful to tumors. For example, mutations in genes that encode proteins may prevent the proteins from folding correctly into their usual three-dimensional shapes, or otherwise disrupt how they work. Therefore, Tilk et al. wanted to understand how tumors survive despite accumulating thousands of passenger mutations.
To do so, Tilk et al. analyzed the activities of genes in over 10,000 human tumors as they accumulated mutations in protein-coding genes. This analysis revealed that genes encoding regulatory proteins that help to manage incorrectly folded proteins were more active in tumors with many mutations in protein-coding genes compared with tumors with fewer mutations in such genes. Further experiments in cancer cells grown in a laboratory demonstrated that these mechanisms that degrade and refold abnormal proteins, are essential for cancer survival.
The findings indicate that, while cancer cells survive by acquiring mutations that promote their growth, they must also contend with harmful mutations that may disrupt how their proteins work. Balancing the production and degradation of proteins is critical for cancer cells to survive. Identifying how to disrupt this balance could be used to develop new cancer treatments in the future.
