Aneuploid embryonic stem cells drive teratoma metastasis

Rong Xiao, Deshu Xu, Meili Zhang, Zhanghua Chen, Li Cheng, Songjie Du, Mingfei Lu, Tonghai Zhou, Ruoyan Li, Fan Bai () and Yue Huang ()
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Rong Xiao: Peking Union Medical College
Deshu Xu: Peking University
Meili Zhang: Peking Union Medical College
Zhanghua Chen: Peking University
Li Cheng: Peking Union Medical College
Songjie Du: Peking Union Medical College
Mingfei Lu: Peking Union Medical College
Tonghai Zhou: Peking Union Medical College
Ruoyan Li: Wellcome Genome Campus
Fan Bai: Peking University
Yue Huang: Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis.

Date: 2024
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DOI: 10.1038/s41467-024-45265-4

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