A team led by researchers from Montreal Neurological Institute and Hospital at McGill University, Canada recently revealed a new mechanism underlying the spread of epithelial cancers. The study was published in The Journal of Cell Biology and is entitled “DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior.”
Metastasis is the major cause of cancer death. It corresponds to the process by which cancer spreads from one organ to other parts of the body and depends on two acquired features of cancer cells — motility and the ability to invade another organ.
In this study, a protein named DENND2B, known to play an important role in normal cell migration during childhood development, was studied in detail. Researchers found that “DENND2B activates another protein called Rab13, an enzyme that promotes cell migration,” according to the study’s senior author Dr. Peter McPherson in a news release.
Rab13 was found to be highly expressed in several forms of cancer, particularly in epithelial cancers like lung cancer that often metastasize to other organs, although the mechanism by which Rab13 is activated and its role in cancer progression is not clear. “Until now, we didn’t know how Rab13 was activated to initiate cell migration,” noted Dr. McPherson.
Researchers have now found that DENND2B is the protein responsible for Rab13 activation resulting in abnormal cell migration and cancer spread. “It was important to see exactly where in the cell Rab13 was being turned on,” said the first author of the study Maria Ioannou. “Where it’s activated is important for figuring out how it functions. We saw that the DENND2B protein was activating Rab13 at the leading edge of the cell, an important point for cell migration.”
Researchers injected mice with highly aggressive human breast cancer cells that expressed high levels of the Rab13 protein or in which Rab13 was artificially removed. “In the case of the cells with reduced Rab13 levels, the cancer either did not grow at all or formed a smaller tumor,” said Dr. McPherson. “Furthermore, the smaller tumor did not metastasize into other tissue.” The results indicated that the presence of Rab13 protein was crucial for the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo.
Rab13 was found to act as a switch for the activation of cancer cell metastasis. According to the team, this is the first report suggesting that blocking Rab13 activation by DENND2B can be a strategy in future therapies to limit the spread of epithelial cancers such as breast and lung cancer. Further studies are required before this discovery can be considered for clinical trials.