They are the Robinson Crusoes of the intracellular world: lone chromosomes, each marooned in its own “micronucleus” outside the nucleus, and often in cancer cells. In a paper published February 2 in Nature, HMS researchers describe how these micronuclei disrupt the chromosomes within them and produce cancer-causing gene mutations. The findings may point to a vulnerability in cancer cells that could be attacked by new therapies.
“The most common genetic change in cancer is the presence of an incorrect number of intact chromosomes within cancer cells, a condition known as aneuploidy,” says senior author David Pellman, an HMS professor of cell biology and the Margaret M. Dyson Professor of Pediatric Oncology at Dana–Farber Cancer Institute. “Our study shows how aneuploidy—and specifically ‘exiled’ chromosomes—could lead to cancer-causing mutations and has implications for cancer prevention and treatment.”
Pellman’s team found that a chromosome in a micronucleus undergoes inefficient duplication that is out of sync with that of the cell’s other chromosomes. This double whammy damages the chromosome, causing a degree of breakage that has been found in cancer cells generated from cells with micronuclei.
The team also found that these chromosomes appeared to be smashed to bits, a condition that linked the findings to those from studies that describe a phenomenon called chromothripsis. In cancer cells exhibiting chromothripsis, one chromosome of the cell shows massive amounts of breakage and rearrangement, while the remainder of the cell’s genome stays largely intact. In addition, the team found that a third of the time, these pulverized bits are neither discarded nor digested by the cell. Instead they are donated to one of the daughter cells during cell division. The damaged chromosomes, therefore, could be incorporated into the cell’s genome and initiate potential cancer-causing mutations.
Image: Neil Ganem and Karen Crasta