Microphysiological systems to study microenvironment-cell nucleus interaction: importance of tissue geometry and heterogeneity

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Theart of three-dimensional (3D) cell culture is to place cells in an environmentthat facilitates their differentiation into physiologically relevant tissues.The mammary gland was the original model for the development of 3D cellculture. With simple microphysiological systems for this model relying on thepresence of extracellular matrix (ECM) components, we initially showed thatnormal differentiation, illustrated by the formation of a basoapical polarityaxis and cell quiescence, relied on a specific organization of the cellnucleus, including the epigenome, itself under the control of the ECMmicroenvironment. To further explore microenvironment-nucleus interaction, werecently developed two organ-on-a-chip systems. The disease-on-a-chip was used tostudy mechanical influence by creating a model of ductal environment made ofcarved hemichannels. It revealed that the curvature of hemichannels directsnuclear morphometry to such an extent that tumors growing inside this geometry(as they do in vivo ) display distinct sensitivity to anticancer drugs.These findings shed light on previous observation that the expression ofproteins involved in anticancer drug response correlate with nuclearmorphometry and highlight the importance of choosing the appropriate 3D cellculture system for in vitro preclinical screening of drugs. Thegradient-on-a-chip was used to create, via microfluidics, a range ofextracellular concentrations of soluble components within the same culturechamber. With this system, it became apparent that oxidizing molecules presentin the ECM of cancers and suspected to contribute to progression and resistanceto treatment, have an influence on nuclear morphometric features recognized asa sign of aggressiveness; however, oxidizer concentration-mediated phenotypicswitch depends on ECM stiffness. These findings suggest that tissueheterogeneity characterizing cancers is directed by competitive and synergisticinfluences among extracellular factors controlling cell phenotype via an impacton the cell nucleus.