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Updated: Mar 25, 2026
Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
Published on: March 17, 2020
3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but
David Onion1, Richard H Argent2, Alexander M Reece-Smith2
1Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. University of Nottingham Flow Cytometry Facility, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
Abstract:
There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.
Insights
This study introduces a 3D ex vivo assay for drug testing using patient tumors. The assay accurately predicts drug efficacy, especially for non-small cell lung cancer (NSCLC), and reduces animal testing.
Area of Science:
- Oncology
- Drug Discovery
- Preclinical Models
Background:
- Current preclinical models inadequately represent the tumor microenvironment.
- This limitation impacts drug efficacy testing, particularly for molecular-targeted agents.
Purpose of the Study:
- To develop and validate a 3D ex vivo assay for pharmacologic testing using patient-derived tumor tissue.
- To assess drug efficacy in a model that better reflects the tumor microenvironment.
Main Methods:
- Embedding low-passage patient tumor tissue in basement membrane extract with cancer-associated fibroblasts (CAFs).
- Performing pharmacologic testing on various solid tumors, including 30 early-stage non-small cell lung cancer (NSCLC) specimens.
- Comparing 3D ex vivo assay results with patient-matched in vivo models.
Main Results:
- The 3D assay supported growth and drug testing for a range of solid tumors.
- High de novo resistance to standard agents was observed in NSCLC, while HDAC inhibitors showed efficacy.
- Patient-derived CAFs increased resistance to several agents, demonstrating the assay's utility for microenvironment-informed testing.
- 3D ex vivo and in vivo models showed similar drug responses, validating the 3D-Tumor Growth Assay (3D-TGA).
Conclusions:
- The 3D-TGA is a high-throughput screen for patient tumors, closely mimicking clinical scenarios.
- The assay provides a valuable platform for tumor microenvironment-educated drug testing, reducing reliance on animal models.
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