ACS Grantee: Jason Sheltzer, PhD
Institution: The Sheltzer Lab at Cold Spring Harbor Laboratory in New York
Area of Focus: Cancer Drug Discovery
Term: 1/1/20-12/31/23 (Research Scholar Grant) and 2/1/21-1/31/22 (TheoryLab Collaborative Grant)
“For a long time, researchers have focused their attention on uncovering the roles that single genes and single mutations play in cancer. But many cancer cells also harbor changes in chromosome numbers that affect hundreds or thousands of genes at once, a condition known as aneuploidy. I think that aneuploidy is one of the last frontiers of cancer genomics. By creating and studying aneuploid cells, we hope to shed light on why cancers become aneuploid and how it affects tumors’ growth and spread.”–Jason Sheltzer, PhD
The Challenge: Normal cells have 46 chromosomes, but cancer cells often have fewer or extra chromosomes. Some advanced tumors can even have cancer cells with up to 100 chromosomes. A missing or extra copy of chromosomes creates an imbalance called aneuploidy. This imbalance can skew the activity of hundreds or thousands of genes.
Approximately 90% of solid tumors exhibit aneuploidy, and aneuploid tumors are associated with decreased overall survival in patients.
Despite the prevalence of aneuploidy in cancer, scientists have a limited understanding of how aneuploidy affects cancer and how it affects patients’ responses to treatment.
The Research: Jason Sheltzer, PhD, has two current grants from the American Cancer Society (ACS) to help support his work on chromosomal instability in cancer cells.
In earlier work not funded by the ACS, Sheltzer published a high-impact study about how aneuploidy influences the metastasis of colon cancer.
Using a variety of techniques, including CRISPR, and by developing new tools, Sheltzer and his team developed a new, more controlled way to study aneuploidy in colon cancer. They added a single extra copy of specific chromosomes in engineered human cells one at a time, so they were able to study the effect of each change on the biology of colon cancer cells.
They found that increasing the number of specific chromosomes in colon cancer cells had distinct effects on the cancer’s invasive behavior. For instance, they learned the addition of an extra copy of the studied chromosomes had no effect or stopped the growth and spread of colon cancer, with one exception: an extra copy of chromosome 5 helped cancers spread.
Interestingly, when Sheltzer’s team studied patient data, they found that when an extra copy of certain different chromosomes was present, metastasis was stopped.
These aneuploidies were linked with increased survival of patients and were significantly more likely to be lost than duplicated when compared to those aneuploidies linked to poor survival of patients. The presence of these beneficial aneuploidies indicate that the effect of these changes in chromosome numbers are just as complicated in real life as they were in the lab, the authors said.
They concluded there was no evidence that specific aneuploidies are universal metastasis promotors. Instead, the results of each aneuploidy are closely tied to the original tumor type.
Why Does it Matter? An improved understanding of how specific chromosomal changes in cancer cells affect the potential for metastasis may help guide new treatment plans.
For instance, researchers are looking for ways to target aneuploid cancer cells with new treatments that would leave normal cells unharmed. Sheltzer’s ACS-funded work is exploring aneuploid cancer cells and drug resistance.
Plus, because aneuploidy is prevalent in all types of cancer, the impact of this exciting work is not limited to colon cancers and metastasis. Sheltzer’s lab also found that many aneuploidies show distinct links for specific cancers, including gliomas, kidney cancer, and leukemia. With support from the ACS TheoryLab grant, Sheltzer is collaborating with ACS grantee, Rajan Kulkarni, PhD, from Oregon Health Science University, to investigate how aneuploidy contributes to skin cancer (melanoma) drug resistance.