Rxiv mechanobiohttps://www.biorxiv.org/content/10.1101/2025.10.04.679984v1?rss=1 #Mechanics #Cell
Cells dynamically adapt their nuclear volumes and proliferation rates during single to multicellular transitions
Tumour development and progression are associated with biophysical alterations that manifest across multiple spatial scales, from the subcellular to multicellular tissue scale. While cells can dynamically regulate their biophysical properties such as volumes and mechanics in dependence of cell state and function, it is not well understood how cells are controlled in the dense multicellular environment of a developing tumour. Here, we quantitatively monitored cell and nuclear volumes of single cancer cells, while they grew into multicellular tumour spheroids within well-defined, tunable biohybrid polymer hydrogels. We quantitatively showed that the formation of multicellular structures is associated with marked reductions of cellular and nuclear volumes, cell cycle delays as well as cell mechanical alterations, and that these changes are coupled. Single-to-multicellular transitions coincided with a drastic decrease in median nuclear volumes by up to 60%, as well as overall cell volume decrease. The nuclear volume decrease could not be explained by growth-induced compressive stress due to confining microenvironments. Instead, cell cycle adaptions were identified as one significant contributor, with smaller-sized G1 cells accumulating in growing clusters, an effect which could be reversed by pharmacological inhibition of CDK1. In addition to cell cycle shifts, cells within spheroids had a higher mass density and were stiffer, which could be reverted upon cell release from clusters. In turn, multicellular-to-single cell transitions that happened in cells that invaded from a tumour spheroid into the surrounding matrix, were accompanied by nuclear volume increases and cell softening. Taken together, our study provides insights into how cells dynamically adapt their cellular/nuclear volumes, cell cycle progression and mechanics in dependence of the multicellular state. ### Competing Interest Statement Raimund Schluessler is employed at CellSense, a company that develops and sells Brillouin microscopes German Research Society, TA 751/4-1, AL 1705/11-1 German Cancer Aid, Mildred Scheel Nachwuchszentrum Dresden IP3
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