Related Experiment Video

Updated: May 7, 2026

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

4.1K

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

María Ramos Zapatero1, Alexander Tong2, James W Opzoomer1

  • 1Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London WC1E 6DD, UK.

Cell
|December 8, 2023
PubMed

Insights

We developed a mass cytometry platform and analysis method to study colorectal cancer (CRC) organoids and their microenvironment. This reveals how cancer-associated fibroblasts (CAFs) protect CRC cells from chemotherapy by altering stem cell states.

Area of Science:

  • Oncology
  • Biotechnology
  • Cell Biology

Background:

  • Patient-derived organoids (PDOs) are valuable for modeling personalized cancer therapy responses.
  • Current screening methods lack the resolution to uncover drug mechanisms or the influence of tumor microenvironment cells on therapeutic outcomes.

Purpose of the Study:

  • To develop a high-throughput platform for analyzing drug response mechanisms in colorectal cancer (CRC) PDOs and their associated stromal cells.
  • To investigate the impact of cancer-associated fibroblasts (CAFs) on CRC cell plasticity and therapeutic resistance.

Main Methods:

  • Utilized a highly multiplexed mass cytometry platform to assess post-translational modification (PTM) signaling, DNA damage, cell-cycle status, and apoptosis in >2,500 CRC PDOs and CAFs.
  • Developed "Trellis," a scalable, tree-based analysis method for comparing patient- and microenvironment-specific drug responses at single-cell resolution.

Main Results:

  • Single-cell screening identified common on-target drug effects like cell-cycle blockage and DNA damage, even in drug-resistant PDOs.
  • Drug-induced apoptosis was found to be rarer, patient-specific, and correlated with cancer cell PTM signaling.
  • Demonstrated that CAFs can induce plasticity in CRC stem cells, shifting them from proliferative (proCSCs) to slow-cycling (revCSCs) states, thereby conferring chemotherapy resistance.

Conclusions:

  • The developed platform and Trellis method enable deep mechanistic insights into drug responses within the complex tumor microenvironment.
  • Understanding CAF-mediated protection mechanisms is crucial for developing novel therapeutic strategies against chemoresistant colorectal cancer.
Keywords:
CAFsPDOsPTM signalingTrelliscancer associated fibroblastschemoresistancemass cytometrypatient-derived organoidsplasticityscRNA-seqsingle-cell screening

More Related Videos

Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis12:41

Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis

Published on: December 23, 2022

4.9K
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing05:35

Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing

Published on: September 15, 2023

1.6K

Related Concept Videos

Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment01:08

Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment

Hepatic impairment, characterized by decreased liver function, does not uniformly mandate adjustments in drug dosage. Whether dosage modifications are necessary depends on various factors related to the drug's metabolism and elimination pathways. If a drug is primarily excreted via the kidneys and bypasses significant hepatic processing, if it undergoes minimal metabolic transformation in the liver, or if it is volatile and primarily expelled through the lungs, dose adjustments may not be...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Drug toxicity: Idiosyncratic Reactions01:16

Drug toxicity: Idiosyncratic Reactions

Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...