Aneuploid Embryonic Stem Cells Drive Teratoma Metastasis

Authors

Rong Xiao
Deshu Xu
Meili Zhang
Zhanghua Chen
Li Cheng
Songjie Du
Mingfei Lu
Tonghai Zhou
Ruoyan Li
Fan Bai
Yue Huang

Publication Date

2-5-2024

Journal

Nature Communications

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.

Keywords

Humans, Animals, Mice, DNA Copy Number Variations, Proteasome Endopeptidase Complex, Aneuploidy, Embryonic Stem Cells, Teratoma

Comments

Supplementary Materials

Data Availability Statement

PMID: 38316790