Abstract
.Significance: Accessible tools are needed for rapid, non-destructive imaging of patient-derived cancer organoid (PCO) treatment response to accelerate drug discovery and streamline treatment planning for individual patients.Aim: To segment and track individual PCOs with wide-field one-photon redox imaging to extract morphological and metabolic variables of treatment response.Approach: Redox imaging of the endogenous fluorophores, nicotinamide dinucleotide (NADH), nicotinamide dinucleotide phosphate (NADPH), and flavin adenine dinucleotide (FAD), was used to monitor the metabolic state and morphology of PCOs. Redox imaging was performed on a wide-field one-photon epifluorescence microscope to evaluate drug response in two colorectal PCO lines. An automated image analysis framework was developed to track PCOs across multiple time points over 48 h. Variables quantified for each PCO captured metabolic and morphological response to drug treatment, including the optical redox ratio (ORR) and organoid area.Results: The ORR (NAD(P)H/(FAD + NAD(P)H)) was independent of PCO morphology pretreatment. Drugs that induced cell death decreased the ORR and growth rate compared to control. Multivariate analysis of redox and morphology variables identified distinct PCO subpopulations. Single-organoid tracking improved sensitivity to drug treatment compared to pooled organoid analysis.Conclusions: Wide-field one-photon redox imaging can monitor metabolic and morphological changes on a single organoid-level, providing an accessible, non-destructive tool to screen drugs in patient-matched samples.
Highlights
Precision medicine aims to improve cancer treatment by matching optimal therapies for each patient, typically based on genomic mutations.[1,2,3] effective for a subset of mutationsJournal of Biomedical OpticsDownloaded From: https://www.spiedigitallibrary.org/journals/Journal-of-Biomedical-Optics on 10 Nov 2021 Terms of Use: https://www.spiedigitallibrary.org/terms-of-useMarch 2021 Vol 26(3)Gil, Deming, and Skala: Patient-derived cancer organoid tracking with wide-field one-photon. . .(e.g., the genes EGFR in lung cancer and BRAF in melanoma), this approach has not been as successful in all cancers.[4]
patient-derived cancer organoid (PCO) capture the cellular heterogeneity found in tumors, which can result in treatment failure if drug resistant cell subpopulations are present.[5,10,12,13]
This study shows that wide-field one-photon redox imaging provides automated assessment of multiple quantitative variables at the organoid-level that capture drug response and separate PCO subpopulations based on phenotype
Summary
(e.g., the genes EGFR in lung cancer and BRAF in melanoma), this approach has not been as successful in all cancers.[4] Alternatively, drugs can be directly tested on a patient’s tumor cells, providing functional information on drug sensitivity that is complementary to genomic approaches.[4] Patient-derived cancer organoids (PCOs) are 3D organotypic cultures grown from fresh tumor samples (e.g., surgery and biopsy). PCOs recapitulate the in vivo molecular, histopathological, and phenotypic features of the original patient tumor.[5,6,7] PCOs provide accurate models of patient drug sensitivity, so that multiple drugs can be screened in patient-matched samples for streamlined drug development and clinical treatment planning.[5,6,8,9,10,11] PCOs capture the cellular heterogeneity found in tumors, which can result in treatment failure if drug resistant cell subpopulations are present.[5,10,12,13] it is critical to measure drug response across multiple PCOs to capture the response of subpopulations and accurately predict patient response. Many tools to evaluate drug response in PCOs, such as single-cell
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