A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

  • EMBO Mol Med. 2022 Mar 7;14(3):e14552. doi: 10.15252/emmm.202114552.
Lucía Zhu  1 ,  Diana Retana  1 ,  Pedro García-Gómez  1 ,  Laura Álvaro-Espinosa  1 ,  Neibla Priego  1 ,  Mariam Masmudi-Martín  1 ,  Natalia Yebra  1 ,  Lauritz Miarka  1 ,  Elena Hernández-Encinas  2 ,  Carmen Blanco-Aparicio  2 ,  Sonia Martínez  2 ,  Cecilia Sobrino  3 ,  Nuria Ajenjo  3 ,  Maria-Jesus Artiga  3 ,  Eva Ortega-Paino  3 ,  Raúl Torres-Ruiz  4  5 ,  Sandra Rodríguez-Perales  4 ,  RENACER ,   Riccardo Soffietti  6 ,  Luca Bertero  7 ,  Paola Cassoni  7 ,  Tobias Weiss  8 ,  Javier Muñoz  9 ,  Juan Manuel Sepúlveda  10 ,  Pedro González-León  11 ,  Luis Jiménez-Roldán  11  12  13 ,  Luis Miguel Moreno  11 ,  Olga Esteban  11 ,  Ángel Pérez-Núñez  11  12  14 ,  Aurelio Hernández-Laín  13 ,  Oscar Toldos  13 ,  Yolanda Ruano  15  16 ,  Lucía Alcázar  17 ,  Guillermo Blasco  17 ,  José Fernández-Alén  17 ,  Eduardo Caleiras  18 ,  Miguel Lafarga  19 ,  Diego Megías  20 ,  Osvaldo Graña-Castro  21 ,  Carolina Nör  22 ,  Michael D Taylor  22 ,  Leonie S Young  23 ,  Damir Varešlija  23 ,  Nicola Cosgrove  23 ,  Fergus J Couch  24 ,  Lorena Cussó  25  26  27  28 ,  Manuel Desco  25  26  27  28 ,  Silvana Mouron  29 ,  Miguel Quintela-Fandino  29 ,  Michael Weller  8 ,  Joaquín Pastor  2 ,  Manuel Valiente  1
Affiliations
  • 1. Brain Metastasis Group, CNIO, Madrid, Spain.
  • 2. Experimental Therapeutics Programme, CNIO, Madrid, Spain.
  • 3. Biobank, CNIO, Madrid, Spain.
  • 4. Molecular Cytogenetics Unit, CNIO, Madrid, Spain.
  • 5. Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT), Madrid, Spain.
  • 6. Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy.
  • 7. Department of Medical Sciences, University of Turin, Turin, Italy.
  • 8. Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
  • 9. Proteomics Unit, ProteoRedISCIII, CNIO, Madrid, Spain.
  • 10. Neuro-Oncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 11. Neurosurgery Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 12. Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain.
  • 13. Neuropathology Unit, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 14. Neuro-Oncology Group, Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain.
  • 15. Pathology Department, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 16. Universidad Francisco de Vitoria, Madrid, Spain.
  • 17. Neurosurgery Department, Hospital Universitario de La Princesa, Madrid, Spain.
  • 18. Histopathology Unit, CNIO, Madrid, Spain.
  • 19. Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria-IDIVAL, Santander, Spain.
  • 20. Confocal Microscopy Unit, CNIO, Madrid, Spain.
  • 21. Bioinformatics Unit, CNIO, Madrid, Spain.
  • 22. Developmental and Stem Cell Biology Program and The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • 23. Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
  • 24. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • 25. Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Madrid, Spain.
  • 26. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
  • 27. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
  • 28. Unidad de Imagen Avanzada, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 29. Breast Cancer Clinical Research Unit, CNIO, Madrid, Spain.
PMID: 35174975 DOI: 10.15252/emmm.202114552
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
drug-screen; metastasis; organotypic cultures; patient-derived; resistance.
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