The drug-induced phenotypic landscape of colorectal cancer organoids.

Autor:	Betge J; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany.; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Germany.; DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Rindtorff N; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Sauer J; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany.; German Cancer Research Center (DKFZ), Computational Genome Biology Group, Heidelberg, Germany., Rauscher B; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Dingert C; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Gaitantzi H; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Herweck F; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Srour-Mhanna K; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Germany.; DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany., Miersch T; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Valentini E; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Boonekamp KE; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Hauber V; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Gutting T; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany.; Department of Internal Medicine IV, Heidelberg University, Heidelberg, Germany., Frank L; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany., Belle S; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Gaiser T; Mannheim Cancer Center, Mannheim, Germany.; Heidelberg University, Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany., Buchholz I; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Jesenofsky R; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Härtel N; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Zhan T; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany.; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Fischer B; German Cancer Research Center (DKFZ), Computational Genome Biology Group, Heidelberg, Germany., Breitkopf-Heinlein K; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Burgermeister E; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany.; Mannheim Cancer Center, Mannheim, Germany., Ebert MP; Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Germany. matthias.ebert@medma.uni-heidelberg.de.; DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. matthias.ebert@medma.uni-heidelberg.de.; Mannheim Cancer Center, Mannheim, Germany. matthias.ebert@medma.uni-heidelberg.de., Boutros M; German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany. m.boutros@dkfz.de.; German Cancer Consortium (DKTK), Heidelberg, Germany. m.boutros@dkfz.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2022 Jun 06; Vol. 13 (1), pp. 3135. Date of Electronic Publication: 2022 Jun 06.
DOI:	10.1038/s41467-022-30722-9
Abstrakt:	Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. (© 2022. The Author(s).)
Databáze:	MEDLINE
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