Aneuploidy of chromosome 8 promotes the mesenchymal lineage during cell fate transitions

Aneuploidy is present in about 90% human solid tumors. Certain tumors remain addicted to aneuploidy. Paradoxically, artificially induced aneuploidy in normal cells elicits cellular stresses and decreases cell fitness. How aneuploidy initially emerges during tumorigenesis is thus unclear. Using human embryonic stem cells (ESCs) as a model, we show that aneuploid ESCs form immature teratomas with an enrichment of mesenchymal tissues. Specifically, chromosome 8 (chr8) gain, a prevalent form of aneuploidy in human cancers, promotes the expansion of mesenchymal stem cells (MSCs) in teratomas and MSC proliferation in vitro. We further show that human embryonal rhabdomyosarcomas, tumors of mesenchymal origin, lack dominant driver mutations but frequently harbor chr8 gain. Our study suggests a plausible mechanism for aneuploidy emergence during tumorigenesis, links specific aneuploidy to the mesenchymal lineage, and paves the way for identifying vulnerabilities of aneuploid MSCs, which may have important roles in tumorigenesis.