The drug-induced phenotypic landscape of colorectal cancer organoids

Johannes Betge, Niklas Rindtorff, Jan Sauer, Benedikt Rauscher, Clara Dingert, Haristi Gaitantzi, Frank Herweck, Kauthar Srour-Mhanna, Thilo Miersch, Erica Valentini, Kim E. Boonekamp, Veronika Hauber, Tobias Gutting, Larissa Frank, Sebastian Belle, Timo Gaiser, Inga Buchholz, Ralf Jesenofsky, Nicolai Härtel, Tianzuo Zhan, Bernd Fischer, Katja Breitkopf-Heinlein, Elke Burgermeister, Matthias P. Ebert () and Michael Boutros ()
Additional contact information
Johannes Betge: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Niklas Rindtorff: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Jan Sauer: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Benedikt Rauscher: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Clara Dingert: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Haristi Gaitantzi: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Frank Herweck: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Kauthar Srour-Mhanna: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Thilo Miersch: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Erica Valentini: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Kim E. Boonekamp: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Veronika Hauber: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Tobias Gutting: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Larissa Frank: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Sebastian Belle: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Timo Gaiser: Mannheim Cancer Center
Inga Buchholz: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Ralf Jesenofsky: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Nicolai Härtel: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Tianzuo Zhan: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology
Bernd Fischer: Computational Genome Biology Group
Katja Breitkopf-Heinlein: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Elke Burgermeister: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Matthias P. Ebert: Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim
Michael Boutros: Division Signaling and Functional Genomics, and Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30722-9

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