title: Compressive stress inhibits proliferation in tumor spheroids through a volume limitation.
abstract: In most instances, the growth of solid tumors occurs in constrained environments and requires a competition for space. A mechanical crosstalk can arise from this competition. In this article, we dissect the biomechanical sequence caused by a controlled compressive stress on multicellular spheroids (MCSs) used as a tumor model system. On timescales of minutes, we show that a compressive stress causes a reduction of the MCS volume, linked to a reduction of the cell volume in the core of the MCS. On timescales of hours, we observe a reversible induction of the proliferation inhibitor, p27Kip1, from the center to the periphery of the spheroid. On timescales of days, we observe that cells are blocked in the cell cycle at the late G1 checkpoint, the restriction point. We show that the effect of pressure on the proliferation can be antagonized by silencing p27Kip1. Finally, we quantify a clear correlation between the pressure-induced volume change and the growth rate of the spheroid. The compression-induced proliferation arrest that we studied is conserved for five cell lines, and is completely reversible. It demonstrates a generic crosstalk between mechanical stresses and the key players of cell cycle regulation. Our results suggest a role of volume change in the sensitivity to pressure, and that p27Kip1 is strongly influenced by this change.
authors.affiliation: Physicochimie Curie (Institut Curie/Centre National de la Recherche Scientifique-UMR168/Université Pierre et Marie Curie), Institut Curie, Centre de Recherche, Paris, France. Electronic address: morgan.delarue@berkeley.edu.
authors.forename: Morgan
authors.initials: M
authors.lastname: Delarue
authors.affiliation: Matière et Système Complexes (Université Paris-Diderot/Centre National de la Recherche Scientifique-UMR 7057), Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Montel
authors.affiliation: Institut Curie/Centre National de la Recherche Scientifique-UMR144 /Université Pierre et Marie Curie, Institut Curie, Centre de Recherche, Paris, France.
authors.forename: Danijela
authors.initials: D
authors.lastname: Vignjevic
authors.affiliation: Physicochimie Curie (Institut Curie/Centre National de la Recherche Scientifique-UMR168/Université Pierre et Marie Curie), Institut Curie, Centre de Recherche, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Prost
authors.affiliation: Physicochimie Curie (Institut Curie/Centre National de la Recherche Scientifique-UMR168/Université Pierre et Marie Curie), Institut Curie, Centre de Recherche, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Joanny
authors.affiliation: Physicochimie Curie (Institut Curie/Centre National de la Recherche Scientifique-UMR168/Université Pierre et Marie Curie), Institut Curie, Centre de Recherche, Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cappello
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D048429:Cell Size; D019245:Compressive Strength; D059585:G1 Phase Cell Cycle Checkpoints; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D018874:Spheroids, Cellular / Q000166:cytology / Q000502:physiology*