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

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

  • Cell. 2023 Dec 7;186(25):5606-5619.e24. doi: 10.1016/j.cell.2023.11.005.
María Ramos Zapatero 1,  Alexander Tong 2,  James W Opzoomer 1,  Rhianna O'Sullivan 1,  Ferran Cardoso Rodriguez 1,  Jahangir Sufi 1,  Petra Vlckova 1,  Callum Nattress 1,  Xiao Qin 1,  Jeroen Claus 3,  Daniel Hochhauser 4,  Smita Krishnaswamy 5,  Christopher J Tape 6
Affiliations

Affiliations

  • 1 Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London WC1E 6DD, UK.
  • 2 Department of Computer Science, Yale University, New Haven, CT, USA; Department of Computer Science and Operations Research, Université de Montréal, Montreal, QC, Canada; Mila - Quebec AI Institute, Montréal, QC, 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 WC1E 6DD, UK.
  • 5 Department of Computer Science, Yale University, New Haven, CT, USA; Department of Genetics, Yale University, New Haven, CT, USA; Program for Computational Biology & Bioinformatics, Yale University, New Haven, CT, USA; Program for Applied Math, Yale University, New Haven, CT, USA; Wu-Tsai Institute, Yale University, New Haven, CT, USA. Electronic address: smita.krishnaswamy@yale.edu.
  • 6 Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London WC1E 6DD, UK. Electronic address: c.tape@ucl.ac.uk.
PMID: 38065081 DOI: 10.1016/j.cell.2023.11.005
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.

Keywords

CAFs; PDOs; PTM signaling; Trellis; cancer associated fibroblasts; chemoresistance; mass cytometry; patient-derived organoids; plasticity; scRNA-seq; single-cell screening.

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