TY - JOUR T1 - Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis JF - bioRxiv DO - 10.1101/854885 SP - 854885 AU - Kevin Kleffman AU - Grace Levinson AU - Eitan Wong AU - Francisco Galán-Echevarría AU - Richard Von-Itter AU - Indigo Rose AU - Lili Blumenberg AU - Alfredo Floristán AU - James Tranos AU - Diana Argibay AU - Jenny Chen AU - Avantika Dhabaria AU - Eleazar de Miera Sainz de Vega AU - Robert Rogers AU - Youssef Zaim-Wadghiri AU - Paul Mathews AU - Iman Osman AU - Kelly Ruggles AU - Beatrix Ueberheide AU - Shane A. Liddelow AU - Ronald DeMattos AU - Yue Ming Li AU - Robert J. Schneider AU - Eva Hernando Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/26/854885.abstract N2 - Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain.Here, we show that melanoma cells require amyloid beta (Aβ), a polypeptide heavily implicated in Alzheimer’s disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete Aβ, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of Aβ decreases brain metastatic burden.Our results reveal a mechanistic connection between brain metastasis and Alzheimer’s disease – two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. ER -