Cancer cells may become, in effect, streamlined and poised to migrate because of a previously overlooked protein interaction. This interaction involves an enzyme that promotes cell migration, Rab13, and a signaling protein, DENND2B.
Rab13, it had been known, could facilitate cancer metastasis. But it had been unclear how, exactly, Rab13 could participate in cancer's progression. Now, thanks to research conducted by scientists at McGill University, it appears that Rab13 is activated by DENND2B, which likely plays a role in the normal migration of cells during childhood development. In adults, cell migration is greatly reduced, but in the case of cancer, unwanted cell migration may occur, contributing to metastasis.
McGill University Researchers, led by Peter McPherson, Ph.D., identified DENND2B as the guanine nucleotide exchange factor for Rab13. They also developed a novel Förster resonance energy transfer-based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells.
Maria Ioannou, a graduate student in Dr. McPherson's laboratory, found that Rab13 has an unusually high degree of expression in many forms of cancer, especially epithelial cancers that often metastasize to the brain.
“It was important to see exactly where in the cell Rab13 was being turned on,” said 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.”
The McGill team’s results appeared February 23 in the Journal of Cell Biology, in an article entitled, “DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior.”
“DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cell’s leading edge,” the authors explained. “Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo.”
In earlier work, Dr. McPherson’s lab, in collaboration with Dr. Morag Park at the Goodman Cancer Centre at McGill University, injected highly aggressive human breast cancer cells into mice under two conditions—one with cells having high levels of Rab13 protein, and one 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,” notes Dr. McPherson. “Furthermore, the smaller tumor did not metastasize into other tissue.”
The new work builds on this earlier result. In particular, the new work suggests that blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers.