On one end of the spectrum of genetic mutations that can lead to cancer is a single DNA base pair out of place, while at the other end is a wholesale reordering of one or several chromosomes. Exactly how these genomic alterations come about and promote cancer development is the focus of research for Peter Ly, a cancer biologist at the University of Texas Southwestern Medical Center.
Ly was recruited in 2019 from the Ludwig Institute for Cancer Research and University of California, San Diego, School of Medicine, where he was a postdoctoral researcher in cancer cell biology. A First-Time Tenure-Track Award from CPRIT enabled Ly to return to his Ph.D. alma mater, UT Southwestern.
One well-studied example of how genomic rearrangements can cause cancer involves a swap of genetic material between two chromosomes (9 and 22), known as the Philadelphia chromosome. This rearrangement generates a hybrid protein that becomes stuck in the “on” position, interrupting the stability of the genome and causing the cells to divide uncontrollably. Most cases of leukemia arise from this mutation. Fortunately for those patients, the drug imatinib blocks the action of this aberrant protein and is one of the most clinically beneficial anti-cancer drugs currently on the market.
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On one end of the spectrum of genetic mutations that can lead to cancer is a single DNA base pair out of place, while at the other end is a wholesale reordering of one or several chromosomes. Exactly how these genomic alterations come about and promote cancer development is the focus of research for Peter Ly, a cancer biologist at the University of Texas Southwestern Medical Center.
Ly was recruited in 2019 from the Ludwig Institute for Cancer Research and University of California, San Diego, School of Medicine, where he was a postdoctoral researcher in cancer cell biology. A First-Time Tenure-Track Award from CPRIT enabled Ly to return to his Ph.D. alma mater, UT Southwestern.
One well-studied example of how genomic rearrangements can cause cancer involves a swap of genetic material between two chromosomes (9 and 22), known as the Philadelphia chromosome. This rearrangement generates a hybrid protein that becomes stuck in the “on” position, interrupting the stability of the genome and causing the cells to divide uncontrollably. Most cases of leukemia arise from this mutation. Fortunately for those patients, the drug imatinib blocks the action of this aberrant protein and is one of the most clinically beneficial anti-cancer drugs currently on the market.
Ly is interested in learning about how diverse kinds of chromosomal abnormalities arise and lead to cancer; and in finding new ways to interfere with them.
During his postdoctoral research, Ly discovered that many types of chromosome rearrangements can occur when cell division goes awry. During normal cell division, every pair of duplicated chromosomes splits in two by attaching to structural elements called the mitotic spindle, which can physically pull chromosomes toward opposite ends of the cell. When all goes well, the cell divides, producing two genetically identical daughter cells.
He’s especially interested in a particularly complex chromosomal rearrangement, called “chromothripsis,” when a chromosome essentially shatters into tens or hundreds of pieces. These fragments are then incorrectly reassembled, often with some pieces missing. “It’s very fascinating from a cell biology perspective,” Ly says. “How could such extensive damage be inflicted onto a single chromosome while the rest of the genome is essentially spared?”
Ly suspects that something goes wrong with cell division, and to find out more, his laboratory using genetically altered cancer and non-cancer cells to investigate.
When chromothripsis occurs, DNA sequences that contain tumor suppressors could be deleted, while other changes may augment cancer-causing genes. This shattering seems to be especially prevalent in tumors of the bone, blood, and brain.
Ly says these rearrangements may happen more frequently than we think. “In most cases, it’s a non-event—that is, the cells don’t grow any faster or have any kind of advantage over normal cells,” he says. “In more rare cases, chromothripsis can lead to mutations that allow abnormal cells to proliferate faster than normal ones, and eventually to cancer.”
Chromothripsis is well correlated with mutations or loss of the p53 gene, which affects genome stability and is mutated in more than half of all human cancers. “Once you have a chromosome that shatters, the p53 pathway can halt cell proliferation,” Ly says. “But when you lose p53, cells with heavy DNA damage can continue to proliferate and repair the damage, which is when rearrangements are likely to form.”
Ly’s ultimate goal is to understand more about how these events occur in order to find a therapeutic target to prevent them from happening or a better way to treat them afterward.
Ly received his undergraduate degree in biology from Baylor University and his Ph.D. in cancer biology from UT Southwestern. He left Texas for a postdoctoral fellowship at Ludwig and UCSD in 2013.
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