韩国19禁爱情电影新高峰揭示

  1. Academic Validation
  2. 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.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P9905
    99.70%, EGFR抑制剂