Aneuploid embryonic stem cells drive teratoma metastasis.

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.

An Intracellular Self-Assembly-Driven Uninterrupted ROS Generator Augments 5-Aminolevulinic-Acid-Based Tumor Therapy.

Free radical therapy based on 5-aminolevulinic acid (ALA, a precursor of the photosensitizer protoporphyrin IX (PpIX)) has been approved by the US Food and Drug Administration for clinical tumor treatment. However, PpIX can be quickly converted into photoinactive heme, leading to unexpectedly paused production of free radicals and severely hindering its therapeutic benefits. Here, inspired by the natural biotransformation of ALA (ALA-PpIX-heme), an uninterrupted reactive oxygen species generator (URG) that converts useless heme to peroxidase mimics via intracellular self-assembly is developed. The URG is prepared by enwrapping ALA-loaded polyamide-amine dendrimers in red blood cell membrane vesicles with a further surface modification of G-quadruplex-structured AS1411. The URGs realize "1 O2 -•OH" uninterrupted generation through "recycling waste" in two steps: i) PpIX generates 1 O2 under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H2 O2 conversion into •OH. Interestingly, the specific generation of 1 O2 in mitochondria and •OH in nuclei further augments the free-radical-induced damage. It is demonstrated that URG can continuously produce free radicals for 6 h postirradiation, and shows 3.3-times more than that of the nonassembly group, achieving nearly 80% regression of tumors in vivo.