Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling
3D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and accelerate identification of drug targets and drug testing. However, the complexity of performing assays with such models remains a hurd...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-04-01
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| Series: | SLAS Discovery |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2472555222000119 |
| _version_ | 1818364542537695232 |
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| author | Evan F Cromwell Oksana Sirenko Ekaterina Nikolov Matthew Hammer Courtney K Brock Margarite D Matossian Madlin S Alzoubi Bridgette M Collins-Burow Matthew E Burow |
| author_facet | Evan F Cromwell Oksana Sirenko Ekaterina Nikolov Matthew Hammer Courtney K Brock Margarite D Matossian Madlin S Alzoubi Bridgette M Collins-Burow Matthew E Burow |
| author_sort | Evan F Cromwell |
| collection | DOAJ |
| description | 3D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and accelerate identification of drug targets and drug testing. However, the complexity of performing assays with such models remains a hurdle for their wider adoption. In the present study, we describe methods for processing and multi-functional profiling of tumoroid samples to test compound effects using a novel flowchip system in combination with high content imaging and metabolite analysis. Tumoroids were formed from primary cells isolated from a patient-derived tumor explant, TU-BcX-4IC, that represents metaplastic breast cancer with a triple-negative breast cancer subtype. Assays were performed in a microfluidics-based device (Pu⋅MA System) that allows automated exchange of media and treatments of tumoroids in a tissue culture incubator environment. Multi-functional assay profiling was performed on tumoroids treated with anti-cancer drugs. High-content imaging was used to evaluate drug effects on cell viability and expression of E-cadherin and CD44. Lactate secretion was used to measure tumoroid metabolism as a function of time and drug concentration. Observed responses included loss of cell viability, decrease in E-cadherin expression, and increase of lactate production. Importantly, the tumoroids were sensitive to romidepsin and trametinib, while showed significantly reduced sensitivity to paclitaxel and cytarabine, consistent with the primary tumor response. These methods for multi-parametric profiling of drug effects in patient-derived tumoroids provide an in depth understanding of drug sensitivity of individual tumor types, with important implications for the future development of personalized medicine. |
| first_indexed | 2024-12-13T22:06:02Z |
| format | Article |
| id | doaj.art-434a840853bb4244814deff2f67e2e23 |
| institution | Directory Open Access Journal |
| issn | 2472-5552 |
| language | English |
| last_indexed | 2024-12-13T22:06:02Z |
| publishDate | 2022-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | SLAS Discovery |
| spelling | doaj.art-434a840853bb4244814deff2f67e2e232022-12-21T23:29:49ZengElsevierSLAS Discovery2472-55522022-04-01273191200Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modelingEvan F Cromwell0Oksana Sirenko1Ekaterina Nikolov2Matthew Hammer3Courtney K Brock4Margarite D Matossian5Madlin S Alzoubi6Bridgette M Collins-Burow7Matthew E Burow8Protein Fluidics, Inc., USA; Corresponding author.Molecular Devices, LLC, USAProtein Fluidics, Inc., USAMolecular Devices, LLC, USATulane University School of Medicine, USATulane University School of Medicine, USATulane University School of Medicine, USATulane University School of Medicine, USATulane University School of Medicine, USA3D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and accelerate identification of drug targets and drug testing. However, the complexity of performing assays with such models remains a hurdle for their wider adoption. In the present study, we describe methods for processing and multi-functional profiling of tumoroid samples to test compound effects using a novel flowchip system in combination with high content imaging and metabolite analysis. Tumoroids were formed from primary cells isolated from a patient-derived tumor explant, TU-BcX-4IC, that represents metaplastic breast cancer with a triple-negative breast cancer subtype. Assays were performed in a microfluidics-based device (Pu⋅MA System) that allows automated exchange of media and treatments of tumoroids in a tissue culture incubator environment. Multi-functional assay profiling was performed on tumoroids treated with anti-cancer drugs. High-content imaging was used to evaluate drug effects on cell viability and expression of E-cadherin and CD44. Lactate secretion was used to measure tumoroid metabolism as a function of time and drug concentration. Observed responses included loss of cell viability, decrease in E-cadherin expression, and increase of lactate production. Importantly, the tumoroids were sensitive to romidepsin and trametinib, while showed significantly reduced sensitivity to paclitaxel and cytarabine, consistent with the primary tumor response. These methods for multi-parametric profiling of drug effects in patient-derived tumoroids provide an in depth understanding of drug sensitivity of individual tumor types, with important implications for the future development of personalized medicine.http://www.sciencedirect.com/science/article/pii/S2472555222000119MicrofluidicsTumoroidsHigh-content ImagingMetabolismPatient-derivedDisease modeling |
| spellingShingle | Evan F Cromwell Oksana Sirenko Ekaterina Nikolov Matthew Hammer Courtney K Brock Margarite D Matossian Madlin S Alzoubi Bridgette M Collins-Burow Matthew E Burow Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling SLAS Discovery Microfluidics Tumoroids High-content Imaging Metabolism Patient-derived Disease modeling |
| title | Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling |
| title_full | Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling |
| title_fullStr | Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling |
| title_full_unstemmed | Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling |
| title_short | Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling |
| title_sort | multifunctional profiling of triple negative breast cancer patient derived tumoroids for disease modeling |
| topic | Microfluidics Tumoroids High-content Imaging Metabolism Patient-derived Disease modeling |
| url | http://www.sciencedirect.com/science/article/pii/S2472555222000119 |
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