Jason Sheltzer

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.