Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses
Creators
- 1. Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London, UK
- 2. Department of Computer Science and Operations Research, Université de Montréal, Mila–Quebec AI Institute, Mon-11 treal, Canada
- 3. Phospho Biomedical Animation, The Greenhouse Studio 6, London, N17 9QU, UK
- 4. Drug-DNA Interactions Group, Department of Oncology, University College London Cancer Institute, London, UK
- 5. Department of Computer Science, Yale University, New Haven, CT, USA
Description
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, hierarchical 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 rare, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate cancer cell plasticity — shifting proliferative stem cells to slow-cycling revival stem cells via YAP to protect cancer cells from chemotherapy.
This repo contains the processed scRNA-seq Scanpy AnnData objects generated from the study. More information describing the data can be found at: https://github.com/TAPE-Lab/Ramos-et-al-Trellis
Files
Files
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