Laura Alvaro-Espinosa, Angel Marquez-Galera, Neibla Priego, Virginia García-Calvo, Maria Perea-García, Carolina Hernandez-Oliver, Diana Retana, Oliva Sanchez, Ana de Pablos-Aragoneses, Pedro García-Gómez, Osvaldo Graña-Castro, Óscar Lapuente-Santana, Laura Serrano-Ron, Fatima Al-Shahrour, Ana Cayuela López, Isabel Peset, Diego Megías, Mihaela Ola, Damir Varešlija, Leonie S. Young, Yolanda Martí-Mateos, Jose A. Enríquez, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Maria S. Soengas, Juergen Bernhagen, Alejandro Antón-Fernández, Jesús Ávila, Miguel A. Marchena, Maximiliano Torres, Fernando de Castro, Mar Márquez-Ropero, Amanda Sierra, Jose P. Lopez-Atalaya, RENACER Group, Daniel Alba-Olano, Denisse Alcivar, Inmaculada Almenara, María Arbaiza Martínez, Ángel Amador Arriaga Aragón, María-Jesús Artiga, Patricia Baena Galán, Cristina Barrena-López, Sergi Benavente, Guillermo Blasco García de Andoain, Lourdes Calero Félix, Santiago Cepeda Chafla, Adolfo de la Lama Zaragoza, Pedro David Delgado López, Juan Delgado-Fernández, Ángela Díaz-Piqueras, Begoña Escolano Otín, José A. Fernández Alén, Laura Fernández Cabré, Concepción Fiaño Valverde, Ricardo Gargini, Isabel Gil Aldea, Ana González Piñeiro, Aurelio Hernández-Laín, Javier Hernández-Losa, Alejandra Londoño Quiroz, Elena Martínez Zamorano, Fran Martínez-Ricarte, Elena Martínez-Sáez, Manuela Mollejo Villanueva, Gonzalo M. Múzquiz Rueda, Syonghyun Nam-Cha, Maria-Sonsoles Opazo Rodríguez, Eva Ortega-Paino, Carmen Ortega-Sabater, Mar Pascual-Llorente, Ángel Pérez-Nuñez, Gerard Plans Ahicart, Santiago Ramón y Cajal, Ángel Rodríguez de Lope Llorca, Juan M. Sepúlveda-Sánchez, Marta Sesé Faustino, Cecilia Sobrino, Óscar Toldos González, Kelly Vargas-Osorio, Manuel Valiente
The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. In this study, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon γ in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand migration inhibitory factor (MIF) that bound the CD74 receptor and induced its translocation to the nucleus where it activated an NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, although it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease noncanonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders, including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases and possibly other brain disorders. SIGNIFICANCE: A reprogrammable subset of CD74+ microglia/macrophages is a shared population with translational relevance across neurologic diseases that drives pathology in brain metastases. See related commentary by Lee and Kang, p. 3103.