TY - JOUR
T1 - A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis
AU - RENACER
AU - Zhu, Lucía
AU - Retana, Diana
AU - García-Gómez, Pedro
AU - Álvaro-Espinosa, Laura
AU - Priego, Neibla
AU - Masmudi-Martín, Mariam
AU - Yebra, Natalia
AU - Miarka, Lauritz
AU - Hernández-Encinas, Elena
AU - Blanco-Aparicio, Carmen
AU - Martínez, Sonia
AU - Sobrino, Cecilia
AU - Ajenjo, Nuria
AU - Artiga, Maria Jesus
AU - Ortega-Paino, Eva
AU - Torres-Ruiz, Raúl
AU - Rodríguez-Perales, Sandra
AU - Soffietti, Riccardo
AU - Bertero, Luca
AU - Cassoni, Paola
AU - Weiss, Tobias
AU - Muñoz, Javier
AU - Sepúlveda, Juan Manuel
AU - González-León, Pedro
AU - Jiménez-Roldán, Luis
AU - Moreno, Luis Miguel
AU - Esteban, Olga
AU - Pérez-Núñez, Ángel
AU - Hernández-Laín, Aurelio
AU - Toldos, Oscar
AU - Ruano, Yolanda
AU - Alcázar, Lucía
AU - Blasco, Guillermo
AU - Fernández-Alén, José
AU - Caleiras, Eduardo
AU - Lafarga, Miguel
AU - Megías, Diego
AU - Graña-Castro, Osvaldo
AU - Nör, Carolina
AU - Taylor, Michael D.
AU - Young, Leonie S.
AU - Varešlija, Damir
AU - Cosgrove, Nicola
AU - Couch, Fergus J.
AU - Cussó, Lorena
AU - Desco, Manuel
AU - Mouron, Silvana
AU - Quintela-Fandino, Miguel
AU - Weller, Michael
AU - Pastor, Joaquín
N1 - Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/3/7
Y1 - 2022/3/7
N2 - 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.
AB - 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.
KW - drug-screen
KW - metastasis
KW - organotypic cultures
KW - patient-derived
KW - resistance
UR - http://www.scopus.com/inward/record.url?scp=85125882089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125882089&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114552
DO - 10.15252/emmm.202114552
M3 - Article
C2 - 35174975
AN - SCOPUS:85125882089
SN - 1757-4676
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 3
M1 - e14552
ER -