Cancer Biology, Cell Biology
Massachusetts Institute of Technology
Dr. Amon is also a professor at the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology.
Causes and Consequences of Aneuploidy
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 important cellular event 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. Yeast serves as an excellent model because the molecules involved in cell division are very similar to those involved in human cell division.
The second major research effort in the Amon lab involves the question of what happens to cells that, defying chromosome segregation quality controls, have acquired or lost chromosomes and hence are 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 in yeast and mammals. Their analysis revealed that aneuploidy is deleterious at the cellular level, causing cell proliferation defects and various stresses such as proteotoxic and energy stress, and genomic instability.
Currently, the Amon lab is investigating how aneuploidy affects properties of cancer cells such as metastatic potential and chemotherapy resistance in mouse models of human cancers. They are also investigating how karyotypes evolve during tumorigenesis and how they respond to cancer treatments. The Amon lab hopes that these efforts will pave the way for the development of new cancer treatments.
“Our findings have important implications for how one thinks about cancer,” says Amon. “Our data demonstrate that aneuploidy is deleterious for cells. Thus, 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. One focus of the lab is to identify genetic alterations that suppress the adverse effects of aneuploidy. Their analysis is likely to provide key insights into the process of tumorigenesis.”