A Pitt research team recently identified how a single aberrant cell can duplicate to form… A Pitt research team recently identified how a single aberrant cell can duplicate to form cancerous tumors.
The discovery brings about the suggestion that a specific protein mechanism could be the target for the treatment of cancer.
Led by William S. Saunders, an associate professor of biological sciences, the team recently published the results of its two-year research project in the journal “Science.”
Nicholas J. Quintyne, a postdoctoral fellow, and Suzanne M. Gollin, a professor of human genetics at Pitt’s Graduate School of Public Health and co-investigator at the Oral Cancer Center of Discovery at Pitt, are members of Saunders’s team.
“We are a team of scientists working together on a large, multifaceted exploration of genetic and cellular alterations in head and neck and its subset, oral cancer,” Gollin said.
During the project, the team tried to identify what causes the cell division defects in cancer cells. A common and well-known defect is called spindle multipolarity, which is the division of chromosomes into more than two sets.
According to Saunders, the spindle allows chromosomes to divide into two equal sets. A fibrous, mechanical structure, a spindle is “sort of like a series of ropes,” Saunders said, with one “rope” tied to each chromosome.
“Imagine more than two people pulling on the ropes, as an analogy,” Saunders said, explaining that the defect creates more than two poles, or “rope” attachments.
Chromosomes only duplicate once. If there are more than two sets of chromosomes after the division, each cell will not acquire a normal number of chromosomes. When cancer cells divide, they do not divide the chromosomes equally and, consequently, they gain genes that increase growth and proliferation. They can also get rid of genes that inhibit cell proliferation.
But this has been a known problem for more than 100 years. In Saunders’ lab, the team is looking for a solution.
“The main focus of my lab is to determine how cancer cells missegregate their chromosomes and how to turn this information against them,” Saunders said.
Through its research, the team has concluded that a two-step process causes spindle multipolarity: Previously known spindle poles are first amplified, and then the amplified poles uncluster. Before the team did its research, researchers typically assumed that the only important step involved amplification.
The team looked for spindle proteins that were over-expressed in cancer cells and then worked to find why these cells were over-expressed. They found that if they reduced the expression of the protein NuMA, they could eliminate spindle multipolarity in some cancer cell lines.
The other major conclusion of the team’s research involves the protein dynein.
The researchers found that unclustering the poles to make multipolar spindles requires the cells to inhibit the function of dynein. This crosslinks the ropes bound to the chromosomes, which are called microtubules.
“It turns out the extra spindle poles cluster together in normal cells,” Saunders said.
“In cancer cells, dynein appears to be inhibited such that the microtubules are not clustered, and the amplified spindle poles are free to separate, causing the multipolarity,” he added.
The appearance of multipolar spindles, an early part of tumor formation, is strongly associated with the tumor stage.
“The greater the multipolarity, the more advanced the tumor,” Saunders said.
In the future, Saunders said, the team might investigate whether re-establishing dynein activity can correct the defect and make the cancer cells divide normally.
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