Nearly all tumors exhibit a condition known as aneuploidy—their cells contain the wrong number of chromosomes. We’re working to understand how aneuploidy impacts cancer progression, in hopes of developing therapies that can specifically eliminate aneuploid cancers while leaving normal cells unharmed.
Human cancers exhibit a diverse array of genomic gains and losses that alter the dosage of hundreds of genes at once. About 90% of solid tumors display whole-chromosome aneuploidy, while many tumors with diploid karyotypes nonetheless harbor segmental or arm-length aneuploidies that also result in significant gene copy number alterations. Despite the prevalence of aneuploidy in cancer, its functional consequences for cell physiology remain poorly understood. Our work has demonstrated the existence of several surprising phenotypes that are shared among cells with different chromosomal imbalances. We demonstrated that aneuploidy can function as a novel source of genomic instability, as aneuploid cells tend to display elevated levels of mutation, mitotic recombination, and chromosome loss. We have also identified a transcriptional signature of aneuploidy that is associated with cellular stress and slow proliferation, and is found in aneuploid primary and cancer cells across a host of organisms. More recently, we have investigated the link between aneuploidy and cellular transformation. Using a series of genetically-matched euploid and aneuploid cell lines, we have demonstrated that aneuploidy can paradoxically function as a barrier to tumor growth. We are currently continuing our investigation of the role in aneuploidy in cancer. We are also applying CRISPR/Cas9-mediated genome engineering to develop novel mouse models in order to explore the impact of gene dosage alterations on tumor development in vivo.
While aneuploidy is a ubiquitous feature of human tumors, it occurs rarely in somatic cells. Thus, differences between aneuploid and euploid cells may represent crucial therapeutic vulnerabilities in cancer. By identifying phenotypes that are shared among tumors with different aneuploidies, we hope to discover pathways that can be manipulated to selectively eliminate aneuploid cells or to block aneuploidy’s non-cell autonomous effects. Drugs that target these pathways may have broad utility against a wide range of aneuploid cancers, while exhibiting minimal toxicity in euploid tissue.
2019 Presidential Early Career Science and Engineering Award (PECASE)
2019 Damon Runyon-Rachleff Innovation Award
Cancer drugs don’t always work as intended, researchers warn
September 11, 2019
Ten experimental cancer drugs kill tumors in ways that are entirely different than how clinicians thought they did, revealing important insights.
Sheltzer wins Presidential Early Career Award
July 9, 2019
CSHL Fellow Jason Sheltzer is a recipient of the Presidential Early Career Award for Scientists and Engineers for his work in cancer research.
CSHL Fellow Jason Sheltzer wins innovation award
January 25, 2019
CSHL Fellow Jason Sheltzer wins the Damon Runyon-Rachleff Innovation Award for his work on cancer.
The year of CRISPR
December 26, 2018
A look at the various labs across CSHL that utilize CRISPR in their research, and the groundbreaking discoveries they help uncover.
Taking uncertainty out of cancer prognosis
December 11, 2018
CSHL Fellow Jason Sheltzer has analyzed nearly 20,000 cancer patient histories and genetic data to take the guesswork out of prognosis.
The cancer answer that wasn’t
March 15, 2018
We look at the "reproducibility crisis" in science, with a cancer researcher discovering something he didn't expect while experimenting with MELK
Science self-corrects: cancer gene does not pass reproducibility test
February 13, 2018
CSHL Fellow Jason Sheltzer and his research team use CRISPR to discover that MELK is not actually involved in cancer.
What a real-life science test looks like
March 24, 2017
By revealing evidence that contradicts the rationale for a new cancer drug, a pair of student scientists learns firsthand that when you do science.
Relationship between incorrect chromosome number and cancer is reassessed after surprising experiments
January 12, 2017
Pre-malignant aneuploid cells grew more slowly and formed smaller tumors than comparable cells with normal chromosome number, CSHL researchers found.
CSHL Fellow wins 2015 NIH Early Independence Award for cancer research
October 6, 2015
CSHL Lab Fellow Jason Sheltzer won the 2015 Early Independence Award from the National Institutes of Health High Risk, High Reward Research Program
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- VOX – Most cancer drugs fail in testing. This might be a big reason why.
- Stat News – Why so many cancer drugs fail: Genes thought ‘essential’ for tumor survival are not, study finds