A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis
Abstract We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among the...
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Springer Nature
2022-02-01
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| Online Access: | https://doi.org/10.15252/emmm.202114552 |
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| author | Lucía Zhu Diana Retana Pedro García‐Gómez Laura Álvaro‐Espinosa Neibla Priego Mariam Masmudi‐Martín Natalia Yebra Lauritz Miarka Elena Hernández‐Encinas Carmen Blanco‐Aparicio Sonia Martínez Cecilia Sobrino Nuria Ajenjo Maria‐Jesus Artiga Eva Ortega‐Paino Raúl Torres‐Ruiz Sandra Rodríguez‐Perales RENACER Riccardo Soffietti Luca Bertero Paola Cassoni Tobias Weiss Javier Muñoz Juan Manuel Sepúlveda Pedro González‐León Luis Jiménez‐Roldán Luis Miguel Moreno Olga Esteban Ángel Pérez‐Núñez Aurelio Hernández‐Laín Oscar Toldos Yolanda Ruano Lucía Alcázar Guillermo Blasco José Fernández‐Alén Eduardo Caleiras Miguel Lafarga Diego Megías Osvaldo Graña‐Castro Carolina Nör Michael D Taylor Leonie S Young Damir Varešlija Nicola Cosgrove Fergus J Couch Lorena Cussó Manuel Desco Silvana Mouron Miguel Quintela‐Fandino Michael Weller Joaquín Pastor Manuel Valiente Adolfo de la Lama‐Zaragoza Lourdes Calero‐Felix Concepcion Fiaño‐Valverde Pedro David Delgado‐López Antonio Montalvo‐Afonso Mar Pascual‐Llorente Ángela Díaz‐Piqueras SH Nam‐Cha Cristina Barrena López Gerard Plans Ahicart Elena Martínez‐Saez Santiago Ramón y Cajal Pilar Nicolás |
| author_facet | Lucía Zhu Diana Retana Pedro García‐Gómez Laura Álvaro‐Espinosa Neibla Priego Mariam Masmudi‐Martín Natalia Yebra Lauritz Miarka Elena Hernández‐Encinas Carmen Blanco‐Aparicio Sonia Martínez Cecilia Sobrino Nuria Ajenjo Maria‐Jesus Artiga Eva Ortega‐Paino Raúl Torres‐Ruiz Sandra Rodríguez‐Perales RENACER Riccardo Soffietti Luca Bertero Paola Cassoni Tobias Weiss Javier Muñoz Juan Manuel Sepúlveda Pedro González‐León Luis Jiménez‐Roldán Luis Miguel Moreno Olga Esteban Ángel Pérez‐Núñez Aurelio Hernández‐Laín Oscar Toldos Yolanda Ruano Lucía Alcázar Guillermo Blasco José Fernández‐Alén Eduardo Caleiras Miguel Lafarga Diego Megías Osvaldo Graña‐Castro Carolina Nör Michael D Taylor Leonie S Young Damir Varešlija Nicola Cosgrove Fergus J Couch Lorena Cussó Manuel Desco Silvana Mouron Miguel Quintela‐Fandino Michael Weller Joaquín Pastor Manuel Valiente Adolfo de la Lama‐Zaragoza Lourdes Calero‐Felix Concepcion Fiaño‐Valverde Pedro David Delgado‐López Antonio Montalvo‐Afonso Mar Pascual‐Llorente Ángela Díaz‐Piqueras SH Nam‐Cha Cristina Barrena López Gerard Plans Ahicart Elena Martínez‐Saez Santiago Ramón y Cajal Pilar Nicolás |
| author_sort | Lucía Zhu |
| collection | DOAJ |
| description | Abstract We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere. |
| format | Article |
| id | doaj-art-192ccb44b2e3449a849f6353de0e50dd |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-192ccb44b2e3449a849f6353de0e50dd2025-08-20T03:43:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-02-0114312910.15252/emmm.202114552A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasisLucía Zhu0Diana Retana1Pedro García‐Gómez2Laura Álvaro‐Espinosa3Neibla Priego4Mariam Masmudi‐Martín5Natalia Yebra6Lauritz Miarka7Elena Hernández‐Encinas8Carmen Blanco‐Aparicio9Sonia Martínez10Cecilia Sobrino11Nuria Ajenjo12Maria‐Jesus Artiga13Eva Ortega‐Paino14Raúl Torres‐Ruiz15Sandra Rodríguez‐Perales16RENACERRiccardo Soffietti17Luca Bertero18Paola Cassoni19Tobias Weiss20Javier Muñoz21Juan Manuel Sepúlveda22Pedro González‐León23Luis Jiménez‐Roldán24Luis Miguel Moreno25Olga Esteban26Ángel Pérez‐Núñez27Aurelio Hernández‐Laín28Oscar Toldos29Yolanda Ruano30Lucía Alcázar31Guillermo Blasco32José Fernández‐Alén33Eduardo Caleiras34Miguel Lafarga35Diego Megías36Osvaldo Graña‐Castro37Carolina Nör38Michael D Taylor39Leonie S Young40Damir Varešlija41Nicola Cosgrove42Fergus J Couch43Lorena Cussó44Manuel Desco45Silvana Mouron46Miguel Quintela‐Fandino47Michael Weller48Joaquín Pastor49Manuel Valiente50Adolfo de la Lama‐ZaragozaLourdes Calero‐FelixConcepcion Fiaño‐ValverdePedro David Delgado‐LópezAntonio Montalvo‐AfonsoMar Pascual‐LlorenteÁngela Díaz‐PiquerasSH Nam‐ChaCristina Barrena LópezGerard Plans AhicartElena Martínez‐SaezSantiago Ramón y CajalPilar NicolásBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOBrain Metastasis Group, CNIOExperimental Therapeutics Programme, CNIOExperimental Therapeutics Programme, CNIOExperimental Therapeutics Programme, CNIOBiobank, CNIOBiobank, CNIOBiobank, CNIOBiobank, CNIOMolecular Cytogenetics Unit, CNIOMolecular Cytogenetics Unit, CNIODepartment of Neuro‐Oncology, University and City of Health and Science HospitalDepartment of Medical Sciences, University of TurinDepartment of Medical Sciences, University of TurinDepartment of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of ZurichProteomics Unit, ProteoRedISCIII, CNIONeuro‐Oncology Unit, Hospital Universitario 12 de OctubreNeurosurgery Unit, Hospital Universitario 12 de OctubreNeurosurgery Unit, Hospital Universitario 12 de OctubreNeurosurgery Unit, Hospital Universitario 12 de OctubreNeurosurgery Unit, Hospital Universitario 12 de OctubreNeurosurgery Unit, Hospital Universitario 12 de OctubreNeuropathology Unit, Instituto i+12, Hospital Universitario 12 de OctubreNeuropathology Unit, Instituto i+12, Hospital Universitario 12 de OctubrePathology Department, Instituto i+12, Hospital Universitario 12 de OctubreNeurosurgery Department, Hospital Universitario de La PrincesaNeurosurgery Department, Hospital Universitario de La PrincesaNeurosurgery Department, Hospital Universitario de La PrincesaHistopathology Unit, CNIODepartment of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria‐IDIVALConfocal Microscopy Unit, CNIOBioinformatics Unit, CNIODevelopmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenEndocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health SciencesEndocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health SciencesEndocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health SciencesDepartment of Laboratory Medicine and Pathology, Mayo ClinicDepartamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de MadridDepartamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de MadridBreast Cancer Clinical Research Unit, CNIOBreast Cancer Clinical Research Unit, CNIODepartment of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of ZurichExperimental Therapeutics Programme, CNIOBrain Metastasis Group, CNIOAbstract We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.https://doi.org/10.15252/emmm.202114552drug‐screenmetastasisorganotypic culturespatient‐derivedresistance |
| spellingShingle | Lucía Zhu Diana Retana Pedro García‐Gómez Laura Álvaro‐Espinosa Neibla Priego Mariam Masmudi‐Martín Natalia Yebra Lauritz Miarka Elena Hernández‐Encinas Carmen Blanco‐Aparicio Sonia Martínez Cecilia Sobrino Nuria Ajenjo Maria‐Jesus Artiga Eva Ortega‐Paino Raúl Torres‐Ruiz Sandra Rodríguez‐Perales RENACER Riccardo Soffietti Luca Bertero Paola Cassoni Tobias Weiss Javier Muñoz Juan Manuel Sepúlveda Pedro González‐León Luis Jiménez‐Roldán Luis Miguel Moreno Olga Esteban Ángel Pérez‐Núñez Aurelio Hernández‐Laín Oscar Toldos Yolanda Ruano Lucía Alcázar Guillermo Blasco José Fernández‐Alén Eduardo Caleiras Miguel Lafarga Diego Megías Osvaldo Graña‐Castro Carolina Nör Michael D Taylor Leonie S Young Damir Varešlija Nicola Cosgrove Fergus J Couch Lorena Cussó Manuel Desco Silvana Mouron Miguel Quintela‐Fandino Michael Weller Joaquín Pastor Manuel Valiente Adolfo de la Lama‐Zaragoza Lourdes Calero‐Felix Concepcion Fiaño‐Valverde Pedro David Delgado‐López Antonio Montalvo‐Afonso Mar Pascual‐Llorente Ángela Díaz‐Piqueras SH Nam‐Cha Cristina Barrena López Gerard Plans Ahicart Elena Martínez‐Saez Santiago Ramón y Cajal Pilar Nicolás A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis EMBO Molecular Medicine drug‐screen metastasis organotypic cultures patient‐derived resistance |
| title | A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| title_full | A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| title_fullStr | A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| title_full_unstemmed | A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| title_short | A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| title_sort | clinically compatible drug screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis |
| topic | drug‐screen metastasis organotypic cultures patient‐derived resistance |
| url | https://doi.org/10.15252/emmm.202114552 |
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