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.
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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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