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Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses

Ramos Zapatero, María; Tong, Alexander; Opzoomer, James W; O’Sullivan, Rhianna; Cardoso Rodriguez, Ferran; Sufi, Jahangir; Vlckova, Petra; ... Tape, Christopher J; + view all (2023) Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses. Cell , 186 (25) 5606-5619.e24. 10.1016/j.cell.2023.11.005. Green open access

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Abstract

Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed “Trellis”—a highly scalable, tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity—shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.

Type: Article
Title: Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cell.2023.11.005
Publisher version: https://doi.org/10.1016/j.cell.2023.11.005
Language: English
Additional information: © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: patient-derived organoids, PDOs, cancer associated fibroblasts, CAFs, single-cell screening, PTM signaling, Trellis, mass cytometry, scRNA-seq, plasticity, chemoresistance
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10183519
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