Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields)
Glioblastoma (GBM) displays a wide range of inter- and intra-tumoral heterogeneity contributing to therapeutic resistance and relapse. Although Tumor Treating Fields (TTFields) are effective for the treatment of GBM, there is a lack of ex vivo models to evaluate effects on patients’ tumor biology or...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/21/5177 |
| _version_ | 1797468868413751296 |
|---|---|
| author | Vera Nickl Ellina Schulz Ellaine Salvador Laureen Trautmann Leopold Diener Almuth F. Kessler Camelia M. Monoranu Faramarz Dehghani Ralf-Ingo Ernestus Mario Löhr Carsten Hagemann |
| author_facet | Vera Nickl Ellina Schulz Ellaine Salvador Laureen Trautmann Leopold Diener Almuth F. Kessler Camelia M. Monoranu Faramarz Dehghani Ralf-Ingo Ernestus Mario Löhr Carsten Hagemann |
| author_sort | Vera Nickl |
| collection | DOAJ |
| description | Glioblastoma (GBM) displays a wide range of inter- and intra-tumoral heterogeneity contributing to therapeutic resistance and relapse. Although Tumor Treating Fields (TTFields) are effective for the treatment of GBM, there is a lack of ex vivo models to evaluate effects on patients’ tumor biology or to screen patients for treatment efficacy. Thus, we adapted patient-derived three-dimensional tissue culture models to be compatible with TTFields application to tissue culture. Patient-derived primary cells (PDPC) were seeded onto murine organotypic hippocampal slice cultures (OHSC), and microtumor development with and without TTFields at 200 kHz was observed. In addition, organoids were generated from acute material cultured on OHSC and treated with TTFields. Lastly, the effect of TTFields on expression of the Ki67 proliferation marker was evaluated on cultured GBM slices. Microtumors exhibited increased sensitivity towards TTFields compared to monolayer cell cultures. TTFields affected tumor growth and viability, as the size of microtumors and the percentage of Ki67-positive cells decreased after treatment. Nevertheless, variability in the extent of the response was preserved between different patient samples. Therefore, these pre-clinical GBM models could provide snapshots of the tumor to simulate patient treatment response and to investigate molecular mechanisms of response and resistance. |
| first_indexed | 2024-03-09T19:13:28Z |
| format | Article |
| id | doaj.art-9ca1b077e2f148cc8fff17faa3ea98b9 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T19:13:28Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9ca1b077e2f148cc8fff17faa3ea98b92023-11-24T04:00:16ZengMDPI AGCancers2072-66942022-10-011421517710.3390/cancers14215177Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields)Vera Nickl0Ellina Schulz1Ellaine Salvador2Laureen Trautmann3Leopold Diener4Almuth F. Kessler5Camelia M. Monoranu6Faramarz Dehghani7Ralf-Ingo Ernestus8Mario Löhr9Carsten Hagemann10Section Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanyDepartment of Neuropathology, Institute of Pathology, University of Würzburg, 97080 Würzburg, GermanyDepartment of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, 06112 Halle (Saale), GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanySection Experimental Neurosurgery, Department of Neurosurgery, University of Würzburg, 97080 Würzburg, GermanyGlioblastoma (GBM) displays a wide range of inter- and intra-tumoral heterogeneity contributing to therapeutic resistance and relapse. Although Tumor Treating Fields (TTFields) are effective for the treatment of GBM, there is a lack of ex vivo models to evaluate effects on patients’ tumor biology or to screen patients for treatment efficacy. Thus, we adapted patient-derived three-dimensional tissue culture models to be compatible with TTFields application to tissue culture. Patient-derived primary cells (PDPC) were seeded onto murine organotypic hippocampal slice cultures (OHSC), and microtumor development with and without TTFields at 200 kHz was observed. In addition, organoids were generated from acute material cultured on OHSC and treated with TTFields. Lastly, the effect of TTFields on expression of the Ki67 proliferation marker was evaluated on cultured GBM slices. Microtumors exhibited increased sensitivity towards TTFields compared to monolayer cell cultures. TTFields affected tumor growth and viability, as the size of microtumors and the percentage of Ki67-positive cells decreased after treatment. Nevertheless, variability in the extent of the response was preserved between different patient samples. Therefore, these pre-clinical GBM models could provide snapshots of the tumor to simulate patient treatment response and to investigate molecular mechanisms of response and resistance.https://www.mdpi.com/2072-6694/14/21/5177glioblastomaTumor Treating Fields (TTFields)organotypic hippocampal slice cultures (OHSC)organoidstumor slice cultures3D ex vivo models |
| spellingShingle | Vera Nickl Ellina Schulz Ellaine Salvador Laureen Trautmann Leopold Diener Almuth F. Kessler Camelia M. Monoranu Faramarz Dehghani Ralf-Ingo Ernestus Mario Löhr Carsten Hagemann Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) Cancers glioblastoma Tumor Treating Fields (TTFields) organotypic hippocampal slice cultures (OHSC) organoids tumor slice cultures 3D ex vivo models |
| title | Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) |
| title_full | Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) |
| title_fullStr | Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) |
| title_full_unstemmed | Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) |
| title_short | Glioblastoma-Derived Three-Dimensional Ex Vivo Models to Evaluate Effects and Efficacy of Tumor Treating Fields (TTFields) |
| title_sort | glioblastoma derived three dimensional ex vivo models to evaluate effects and efficacy of tumor treating fields ttfields |
| topic | glioblastoma Tumor Treating Fields (TTFields) organotypic hippocampal slice cultures (OHSC) organoids tumor slice cultures 3D ex vivo models |
| url | https://www.mdpi.com/2072-6694/14/21/5177 |
| work_keys_str_mv | AT veranickl glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT ellinaschulz glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT ellainesalvador glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT laureentrautmann glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT leopolddiener glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT almuthfkessler glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT cameliammonoranu glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT faramarzdehghani glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT ralfingoernestus glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT mariolohr glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields AT carstenhagemann glioblastomaderivedthreedimensionalexvivomodelstoevaluateeffectsandefficacyoftumortreatingfieldsttfields |