Chromosome Segregation Fidelity in Epithelia Requires Tissue Architecture

Abstract

Much of our understanding of chromosome segregation is based on cell culture systems. Here, we examine the importance of the tissue environment for chromosome segregation by comparing chromosome segregation fidelity across several primary cell types in native and nonnative contexts. We discover that epithelial cells have increased chromosome missegregation outside of their native tissues. Using organoid culture systems, we show that tissue architecture, specifically integrin function, is required for accurate chromosome segregation. We find that tissue architecture enhances the correction of merotelic microtubule-kinetochore attachments, and this is especially important for maintaining chromosome stability in the polyploid liver. We propose that disruption of tissue architecture could underlie the widespread chromosome instability across epithelial cancers. Moreover, our findings highlight the extent to which extracellular context can influence intrinsic cellular processes and the limitations of cell culture systems for studying cells that naturally function within a tissue.

Oncogenic signaling alters cell shape and mechanics to facilitate cell division under confinement

“…This is also the case in 3D culture, where mitotic rounding generates force in all directions 11 , similar to cells in the tissue context. Environment context is also important for the fidelity of cell division: recent work has shown that primary epithelial cells cultured in 3D suffer fewer chromosome segregation defects than in 2D 37 . Conversely, cell culture in a stiff 3D gel that limits anaphase elongation also induces chromosomal segregation defects 11 .…”

KekuleScope: prediction of cancer cell line sensitivity and compound potency using convolutional neural networks trained on compound images

“…Cultured cancer cell lines are limited disease models in that they do not recapitulate the tumor microenvironment nor interactions with the immune system [1][2][3][4][5][6], fundamental properties of cellular organization are altered in culture [7], and their response to anticancer drugs is affected by both assay heterogeneity [8] and genomic alterations acquired in vitro [9]. However, cancer cell lines still represent versatile models to study fundamental aspects of cancer biology [10,11], and the genomic determinants of drug response [3,[12][13][14].…”

Fast and efficient generation of knock-in human organoids using homology-independent CRISPR/Cas9 precision genome editing

“…A recent study underscored that tissue architecture ensures correct mitotic spindle behaviour. Indeed, 2D cultures of dissociated epithelial cells display mitotic spindle defects opposite to what is observed in cells cultured in a 3D configuration 41 . Human hepatocyte organoids retain cellular polarization, with an apical domain defined by expression of MRP2 and ZO-1, facing the internal bile canaliculus ( Fig.…”

“…6g). These discrepancies could be due to differences in 2D vs 3D culturing of the cells, which has been shown to induce missegregation 41 or alternatively due to mouse-human species differences.…”