EMBO Molecular Medicine (Feb 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,
- 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
Affiliations
- Lucía Zhu
- Brain Metastasis Group, CNIO
- Diana Retana
- Brain Metastasis Group, CNIO
- Pedro García‐Gómez
- Brain Metastasis Group, CNIO
- Laura Álvaro‐Espinosa
- Brain Metastasis Group, CNIO
- Neibla Priego
- Brain Metastasis Group, CNIO
- Mariam Masmudi‐Martín
- Brain Metastasis Group, CNIO
- Natalia Yebra
- Brain Metastasis Group, CNIO
- Lauritz Miarka
- Brain Metastasis Group, CNIO
- Elena Hernández‐Encinas
- Experimental Therapeutics Programme, CNIO
- Carmen Blanco‐Aparicio
- Experimental Therapeutics Programme, CNIO
- Sonia Martínez
- Experimental Therapeutics Programme, CNIO
- Cecilia Sobrino
- Biobank, CNIO
- Nuria Ajenjo
- Biobank, CNIO
- Maria‐Jesus Artiga
- Biobank, CNIO
- Eva Ortega‐Paino
- Biobank, CNIO
- Raúl Torres‐Ruiz
- Molecular Cytogenetics Unit, CNIO
- Sandra Rodríguez‐Perales
- Molecular Cytogenetics Unit, CNIO
- RENACER
- Riccardo Soffietti
- Department of Neuro‐Oncology, University and City of Health and Science Hospital
- Luca Bertero
- Department of Medical Sciences, University of Turin
- Paola Cassoni
- Department of Medical Sciences, University of Turin
- Tobias Weiss
- Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich
- Javier Muñoz
- Proteomics Unit, ProteoRedISCIII, CNIO
- Juan Manuel Sepúlveda
- Neuro‐Oncology Unit, Hospital Universitario 12 de Octubre
- Pedro González‐León
- Neurosurgery Unit, Hospital Universitario 12 de Octubre
- Luis Jiménez‐Roldán
- Neurosurgery Unit, Hospital Universitario 12 de Octubre
- Luis Miguel Moreno
- Neurosurgery Unit, Hospital Universitario 12 de Octubre
- Olga Esteban
- Neurosurgery Unit, Hospital Universitario 12 de Octubre
- Ángel Pérez‐Núñez
- Neurosurgery Unit, Hospital Universitario 12 de Octubre
- Aurelio Hernández‐Laín
- Neuropathology Unit, Instituto i+12, Hospital Universitario 12 de Octubre
- Oscar Toldos
- Neuropathology Unit, Instituto i+12, Hospital Universitario 12 de Octubre
- Yolanda Ruano
- Pathology Department, Instituto i+12, Hospital Universitario 12 de Octubre
- Lucía Alcázar
- Neurosurgery Department, Hospital Universitario de La Princesa
- Guillermo Blasco
- Neurosurgery Department, Hospital Universitario de La Princesa
- José Fernández‐Alén
- Neurosurgery Department, Hospital Universitario de La Princesa
- Eduardo Caleiras
- Histopathology Unit, CNIO
- Miguel Lafarga
- Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria‐IDIVAL
- Diego Megías
- Confocal Microscopy Unit, CNIO
- Osvaldo Graña‐Castro
- Bioinformatics Unit, CNIO
- Carolina Nör
- Developmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
- Michael D Taylor
- Developmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
- Leonie S Young
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences
- Damir Varešlija
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences
- Nicola Cosgrove
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences
- Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic
- Lorena Cussó
- Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid
- Manuel Desco
- Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid
- Silvana Mouron
- Breast Cancer Clinical Research Unit, CNIO
- Miguel Quintela‐Fandino
- Breast Cancer Clinical Research Unit, CNIO
- Michael Weller
- Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich
- Joaquín Pastor
- Experimental Therapeutics Programme, CNIO
- Manuel Valiente
- Brain Metastasis Group, CNIO
- 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
- DOI
- https://doi.org/10.15252/emmm.202114552
- Journal volume & issue
-
Vol. 14,
no. 3
pp. 1 – 29
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
