Wolf-Dankovich, G.; Mashiah, T.; Saad, R.; Somech, E.; Khoury, H.; Tirosh, I.; Ben-David, U.

Aneuploidy poses a central paradox in cancer biology: it impairs cellular fitness in normal cells but drives cancer progression. To resolve this, we analyzed single cell transcriptomes from >665,000 cells - including ~288,000 malignant cells - across 304 tumors and 15 cancer types. Integrating transcriptomics with inferred aneuploidy profiles, we characterized cell-intrinsic programs and interactions with the tumor microenvironment. Unexpectedly, highly aneuploid single cells exhibited reduced proliferation and metabolism, contrasting sharply with tumor-bulk profiles. We show this divergence is driven by karyotypic heterogeneity: in highly heterogeneous tumors, aneuploid cells display signatures of acute stress and negative selection. Conversely, in clonally aneuploid tumors, these detrimental signatures are lost and replaced by signatures of increased proliferation and enhanced metabolism, reflecting adaptation. Additionally, we identified consistent transcriptional programs driven by recurrent chromosome-arm alterations across both single cells and bulk tumors. These findings illuminate the selective forces shaping tumor evolution and the aneuploidy paradox.