2. Academic Validation
  3. Aneuploid embryonic stem cells drive teratoma metastasis

Aneuploid embryonic stem cells drive teratoma metastasis

  • Nat Commun. 2024 Feb 5;15(1):1087. doi: 10.1038/s41467-024-45265-4.
Rong Xiao # 1,  Deshu Xu # 2,  Meili Zhang # 1,  Zhanghua Chen # 2,  Li Cheng 1,  Songjie Du 1,  Mingfei Lu 1,  Tonghai Zhou 1,  Ruoyan Li 3 4,  Fan Bai 5,  Yue Huang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
  • 2 Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, 100871, China.
  • 3 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
  • 4 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, 100871, China. fbai@pku.edu.cn.
  • 6 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. huangyue@pumc.edu.cn.
  • # Contributed equally.
PMID: 38316790 DOI: 10.1038/s41467-024-45265-4
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.

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