The drug-induced phenotypic landscape of colorectal cancer organoids.

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.

• Authors: 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, Michael Boutros
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 3135 (06 06 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35668108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Topics

• Colorectal Neoplasms (genetics)
• Humans
• Organoids (pathology)
• Phenotype
• Signal Transduction