Researchers at Pitt have identified how a single aberrant cell can duplicate to form cancerous tumors, suggesting a specific protein mechanism as a target for the treatment of cancer, they report in a paper titled “Spindle Multipolarity Is Prevented by Centrosomal Clustering,” published in the Jan. 7 issue of Science.

The team, led by William S. Saunders, associate professor of biological sciences in Pitt’s School of Arts and Sciences, found that overexpression of a single protein can cause changes in a cell associated with the formation of tumors.“Virtually all cancer cells acquire the ability to change their genomic structure,” said Saunders. “Researchers in the field are looking for single events that can cause multiple mutational changes to the genome, and this research is an example of that.”

Before a normal cell divides, its chromosomes are duplicated and then pulled apart by a structure called a spindle, so that the two daughter cells each will have the same number of chromosomes. At the end of a normal spindle is the spindle pole, also called the centrosome, which pulls the chromosomes outward. Cancer cells often have extra centrosomes. When a cell has more than two centrosomes, sometimes—but not always—the spindles will have more than one pole and cell division won’t work correctly, leading to the swapping of genetic material, uncontrolled cell division, and the formation of tumors.

Pitt Researchers Perform First Synthesis of Anticancer Compound Pitt researchers have accomplished the first synthesis of the rare natural anticancer compound disorazole, they announced in a paper titled “Total Synthesis of (-)-Disorazole C1,” published in the November issue of the Journal of the American Chemical Society. This synthesis is critical for the continued study and pharmaceutical development of the substance. “We are very excited about the potential of this compound,” said Peter Wipf, Pitt professor of chemistry and director of the Combinatorial Chemistry Center and the Center for Chemical Methodologies and Library Development at Pitt, who coauthored the paper with Pitt chemistry graduate student Tom Graham. “Disorazole is among the most potent antiproliferative agents known.” Disorazole was first identified in 1994 in the fermentation broth of the myxobacterium Sorangium cellulosum, but it is difficult to study in its natural form. Prior to Graham and Wipf’s research, no viable method of synthesizing the compound existed. Pharmaceutical companies have expressed interest in developing disorazole as an anticancer drug. Wipf and Graham are conducting studies of disorazole’s anticancer potential in collaboration with Billy W. Day, associate professor of pharmaceutical sciences in Pitt’s School of Pharmacy. The paper is available online at http://pubs.acs.org. This research was supported by a grant from the National Institutes of Health. —Karen Hoffmann

Why this doesn’t always happen when there are too many centrosomes was the focus of the Pitt researchers’ investigation. They found that as long as the extra centrosomes “cluster” together, the spindles will form normally, with two ends, and the cells will divide normally. “No one else appreciated that that was required, or what the mechanism was that separated them,” said Saunders.

But when the extra centrosomes don’t cluster together, the spindles don’t form normally, and cell division can become unstable, reported Nicholas J. Quintyne, a postdoctoral fellow working with Saunders and first author of the paper.

Investigating the mechanism by which this occurs, the researchers found that in cultured oral cancer cells a protein called dynein is missing from the spindle, and the centrosomes no longer cluster together.

Furthermore, the researchers discovered that in some types of tumors, dynein is inhibited by the overexpression of another protein called NuMA. Excess NuMA seems to prevent dynein from binding to the spindle. When they reduced the level of NuMA in cultured cancer cells, the dynein returned to the spindles, and the spindles were no longer multipolar.

“This finding suggests that a possible treatment for some types of cancer could be a drug that inhibits NuMA,” noted coauthor Susanne M. Gollin, professor of human genetics in Pitt’s Graduate School of Public Health and coinvestigator at the Oral Cancer Center of Discovery at the University of Pittsburgh Cancer Institute. In the future, the researchers plan to look at other proteins that bind to NuMA and how these proteins interact in the process.

The research was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health and by the American Cancer Society.