Millions of cells in our body divide every day to replace cells that are injured, worn out, or dying. While cell division itself is a tightly regulated event, serious errors occasionally occur. The result from such errors, cells with too few or too many chromosomes, is called aneuploidy. This condition is frequently associated with death and disease in humans. Understanding the causes and consequences of aneuploidy is therefore critical for deciphering the basis for many human diseases.
Angelika Amon works to uncover the networks that regulate the accurate segregation of chromosomes during cell division. This information is crucial to understanding not only normal cell division but also the uncontrollable cell division that leads to cancer. In particular, she is probing the way chromosomes are pulled apart as a cell divides to form two new "daughter" cells. "We want to determine how cells make sure their chromosomes separate in the right way," Amon said. "We want to understand how aneuploidy is prevented."
Amon also hopes to determine the mechanisms that ensure accurate chromosome segregation during meiosis. Missteps in the chromosome separation during this cellular division are the leading cause of miscarriages and a major cause of birth defects, due to missing or extra chromosomes. Down syndrome, for example, occurs when an individual inherits three copies of chromosome 21, leading to mental and physical disabilities.
Amon's interest in chromosome segregation sprang from a high school biology class, where she watched an old movie of cells dividing. "I was fascinated by the movement of chromosomes and the apparent order and coordination involved in chromosomes joining and separating during cell division," Amon recalls.
Using the budding yeast Saccharomyces cerevisiae as a model, Amon combines genetic, cell biological, and biochemical techniques to determine the mechanisms that control the cell's progression from one stage of the cell cycle to the next. The yeast serves as an excellent model because the molecules involved in cell division are very similar to those involved in human cell division.
A second major research effort in the Amon lab is focused on what happens to cells in which the chromosome segregation quality controls fail and as a result acquire or lose chromosomes. Cells with an incorrect chromosome number are called aneuploid. In humans, aneuploidy is associated with birth defects and is a key characteristic of cancer. More than 90 percent of all solid human tumors are aneuploid. To begin to understand how aneuploidy causes diseases, Amon and her coworkers analyzed the effects of aneuploidy on normal cell physiology. They created 20 yeast strains that carry one or two additional chromosomes and, subsequently, primary mouse cells that carry four different additional chromosomes. Their analysis revealed that aneuploidy is deleterious for the cell, causing cell proliferation defects in both yeast and mouse. They also discovered that aneuploid yeast and mouse cells share a number of phenotypes that are indicative of proteotoxic and energy stress.
"These findings have important implications for how one thinks about cancer." Amon says. Cancer cells must overcome the adverse effects of aneuploidy in order to outgrow euploid cells and take advantage of potential benefits that arise from the aneuploid condition. Results from Amon's lab further suggest that cancer cells may be more sensitive to conditions that exaggerate the stresses associated with aneuploidy.
The Amon lab has begun to identify genetic alterations that enhance or suppress the adverse effects of aneuploidy. They are also searching for compounds that preferentially inhibit the proliferation of aneuploid mouse cells. So far their search has revealed three compounds with such properties. These compounds also exhibit efficacy against aneuploid cancer cells. They hope that identifying genetic alterations and compounds that suppress or enhance the adverse effects of aneuploidy will provide key insights into how aneuploidy contributes to tumorigenesis.