Abstract SY22-02: Aneuploidy and 3D tissue rigidity

Abstract

Abstract Sequence differences between normal cells of the same person are increasingly evident (e.g. Yizhak Science 2019), and such somatic variations across different tissues increase from liquid to solid tissues, consistent with similar trends across liquid and solid tumors. Further analyses suggest changes increase with high levels of both replication-division (R=0.24) and the stiffness E of each tissue (R=0.6). Chromosome copy number gains and losses – aneuploidy – follow these trends, which prompted our hypothesis that stiff 3d microenvironments could increase aneuploidy of dividing cells moreso than less confining or microenvironments. We developed a method of live-cell monitoring of changes to chromosome copy numbers and used it to study diverse perturbations, particularly compressed mitosis seen in vivo. Many dividing cells die when squeezed, but rare stem cells and cancer cells show heritable loss of mono-allelic, GFP/RFP-tagged constitutive genes that function as Chromosome-reporters (ChReporters). Flattening spreads mitotic chromatin, favors chromosome mis-segregation, and increases ChReporter loss independent of an established spindle assembly checkpoint. Inhibiting the high level of Topoisomerase in such cells impedes chromosome compaction, division, and ChReporter loss, whereas the proposed tumor suppressor Myosin-IIA stabilizes chromatin against fragmentation, with knockdown increasing ChReporter loss. Solid human tumors and teratomas show similar ChReporter trends in mice, and single-cell-sequencing identifies rare chromosome changes exclusively in normal 3D-infiltrative cells while also relating specific chromosome losses to altered growth and motility. 3D rigidity thus gives rise to heritable aneuploidy as a mechanogenetic change. Citation Format: Dennis Discher. Aneuploidy and 3D tissue rigidity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY22-02.