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A quantitative analysis of the interplay of environment, neighborhood, and cell state in 3D spheroids


Zanotelli, Vito R T; Leutenegger, Matthias; Lun, Xiao-Kang; Georgi, Fanny; de Souza, Natalie; Bodenmiller, Bernd (2020). A quantitative analysis of the interplay of environment, neighborhood, and cell state in 3D spheroids. Molecular Systems Biology, 16:e9798.

Abstract

Cells react to their microenvironment by integrating external stimuli into phenotypic decisions via an intracellular signaling network. To analyze the interplay of environment, local neighborhood, and internal cell state effects on phenotypic variability, we developed an experimental approach that enables multiplexed mass cytometric imaging analysis of up to 240 pooled spheroid microtissues. We quantified the contributions of environment, neighborhood, and intracellular state to marker variability in single cells of the spheroids. A linear model explained on average more than half of the variability of 34 markers across four cell lines and six growth conditions. The contributions of cell-intrinsic and environmental factors to marker variability are hierarchically interdependent, a finding that we propose has general implications for systems-level studies of single-cell phenotypic variability. By the overexpression of 51 signaling protein constructs in subsets of cells, we also identified proteins that have cell-intrinsic and cell-extrinsic effects. Our study deconvolves factors influencing cellular phenotype in a 3D tissue and provides a scalable experimental system, analytical principles, and rich multiplexed imaging datasets for future studies.

Abstract

Cells react to their microenvironment by integrating external stimuli into phenotypic decisions via an intracellular signaling network. To analyze the interplay of environment, local neighborhood, and internal cell state effects on phenotypic variability, we developed an experimental approach that enables multiplexed mass cytometric imaging analysis of up to 240 pooled spheroid microtissues. We quantified the contributions of environment, neighborhood, and intracellular state to marker variability in single cells of the spheroids. A linear model explained on average more than half of the variability of 34 markers across four cell lines and six growth conditions. The contributions of cell-intrinsic and environmental factors to marker variability are hierarchically interdependent, a finding that we propose has general implications for systems-level studies of single-cell phenotypic variability. By the overexpression of 51 signaling protein constructs in subsets of cells, we also identified proteins that have cell-intrinsic and cell-extrinsic effects. Our study deconvolves factors influencing cellular phenotype in a 3D tissue and provides a scalable experimental system, analytical principles, and rich multiplexed imaging datasets for future studies.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Immunology and Microbiology
Life Sciences > General Agricultural and Biological Sciences
Physical Sciences > Applied Mathematics
Language:English
Date:December 2020
Deposited On:15 Jan 2021 10:38
Last Modified:01 Feb 2021 16:22
Publisher:European Molecular Biology Organization
ISSN:1744-4292
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/msb.20209798
PubMed ID:33369114

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