EMBO Molecular Medicine (Mar 2022)
A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis
- 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
Affiliations
- Lucía Zhu
- Brain Metastasis Group CNIO Madrid Spain
- Diana Retana
- Brain Metastasis Group CNIO Madrid Spain
- Pedro García‐Gómez
- Brain Metastasis Group CNIO Madrid Spain
- Laura Álvaro‐Espinosa
- Brain Metastasis Group CNIO Madrid Spain
- Neibla Priego
- Brain Metastasis Group CNIO Madrid Spain
- Mariam Masmudi‐Martín
- Brain Metastasis Group CNIO Madrid Spain
- Natalia Yebra
- Brain Metastasis Group CNIO Madrid Spain
- Lauritz Miarka
- Brain Metastasis Group CNIO Madrid Spain
- Elena Hernández‐Encinas
- Experimental Therapeutics Programme CNIO Madrid Spain
- Carmen Blanco‐Aparicio
- Experimental Therapeutics Programme CNIO Madrid Spain
- Sonia Martínez
- Experimental Therapeutics Programme CNIO Madrid Spain
- Cecilia Sobrino
- Biobank CNIO Madrid Spain
- Nuria Ajenjo
- Biobank CNIO Madrid Spain
- Maria‐Jesus Artiga
- Biobank CNIO Madrid Spain
- Eva Ortega‐Paino
- Biobank CNIO Madrid Spain
- Raúl Torres‐Ruiz
- Molecular Cytogenetics Unit CNIO Madrid Spain
- Sandra Rodríguez‐Perales
- Molecular Cytogenetics Unit CNIO Madrid Spain
- RENACER
- Riccardo Soffietti
- Department of Neuro‐Oncology University and City of Health and Science Hospital Turin Italy
- Luca Bertero
- Department of Medical Sciences University of Turin Turin Italy
- Paola Cassoni
- Department of Medical Sciences University of Turin Turin Italy
- Tobias Weiss
- Department of Neurology Clinical Neuroscience Center University Hospital Zurich and University of Zurich Zurich Switzerland
- Javier Muñoz
- Proteomics Unit ProteoRedISCIII CNIO Madrid Spain
- Juan Manuel Sepúlveda
- Neuro‐Oncology Unit Hospital Universitario 12 de Octubre Madrid Spain
- Pedro González‐León
- Neurosurgery Unit Hospital Universitario 12 de Octubre Madrid Spain
- Luis Jiménez‐Roldán
- Neurosurgery Unit Hospital Universitario 12 de Octubre Madrid Spain
- Luis Miguel Moreno
- Neurosurgery Unit Hospital Universitario 12 de Octubre Madrid Spain
- Olga Esteban
- Neurosurgery Unit Hospital Universitario 12 de Octubre Madrid Spain
- Ángel Pérez‐Núñez
- Neurosurgery Unit Hospital Universitario 12 de Octubre Madrid Spain
- Aurelio Hernández‐Laín
- Neuropathology Unit Instituto i+12, Hospital Universitario 12 de Octubre Madrid Spain
- Oscar Toldos
- Neuropathology Unit Instituto i+12, Hospital Universitario 12 de Octubre Madrid Spain
- Yolanda Ruano
- Pathology Department Instituto i+12, Hospital Universitario 12 de Octubre Madrid Spain
- Lucía Alcázar
- Neurosurgery Department Hospital Universitario de La Princesa Madrid Spain
- Guillermo Blasco
- Neurosurgery Department Hospital Universitario de La Princesa Madrid Spain
- José Fernández‐Alén
- Neurosurgery Department Hospital Universitario de La Princesa Madrid Spain
- Eduardo Caleiras
- Histopathology Unit CNIO Madrid Spain
- Miguel Lafarga
- Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) University of Cantabria‐IDIVAL Santander Spain
- Diego Megías
- Confocal Microscopy Unit CNIO Madrid Spain
- Osvaldo Graña‐Castro
- Bioinformatics Unit CNIO Madrid Spain
- Carolina Nör
- Developmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON Canada
- Michael D Taylor
- Developmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON Canada
- Leonie S Young
- Endocrine Oncology Research Group Department of Surgery RCSI University of Medicine and Health Sciences Dublin Ireland
- Damir Varešlija
- Endocrine Oncology Research Group Department of Surgery RCSI University of Medicine and Health Sciences Dublin Ireland
- Nicola Cosgrove
- Endocrine Oncology Research Group Department of Surgery RCSI University of Medicine and Health Sciences Dublin Ireland
- Fergus J Couch
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA
- Lorena Cussó
- Departamento de Bioingeniería e Ingeniería Aeroespacial Universidad Carlos III de Madrid Madrid Spain
- Manuel Desco
- Departamento de Bioingeniería e Ingeniería Aeroespacial Universidad Carlos III de Madrid Madrid Spain
- Silvana Mouron
- Breast Cancer Clinical Research Unit CNIO Madrid Spain
- Miguel Quintela‐Fandino
- Breast Cancer Clinical Research Unit CNIO Madrid Spain
- Michael Weller
- Department of Neurology Clinical Neuroscience Center University Hospital Zurich and University of Zurich Zurich Switzerland
- Joaquín Pastor
- Experimental Therapeutics Programme CNIO Madrid Spain
- Manuel Valiente
- Brain Metastasis Group CNIO Madrid Spain
- DOI
- https://doi.org/10.15252/emmm.202114552
- Journal volume & issue
-
Vol. 14,
no. 3
pp. n/a – n/a
Abstract
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.
Keywords