Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
| Autor: | Eva Hernando, Ronald DeMattos, Paul M. Mathews, Beatrix Ueberheide, Kelly V. Ruggles, Indigo V.L. Rose, Grace Levinson, Francisco Galán-Echevarría, Richard Von-Itter, Iman Osman, James Tranos, Shane A. Liddelow, Youssef Zaim-Wadghiri, Lili Blumenberg, Yue-Ming Li, Alfredo Floristán, Kevin Kleffman, Avantika Dhabaria, Diana Argibay, Eleazar de Miera Sainz de Vega, Eitan Wong, Robert J. Schneider, Robert Rogers, Jenny Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Amyloid beta business.industry Melanoma Cancer medicine.disease Phenotype 3. Good health 03 medical and health sciences 0302 clinical medicine Parenchyma Cancer cell Cancer research medicine biology.protein business 030217 neurology & neurosurgery Neuroinflammation 030304 developmental biology Brain metastasis |
| DOI: | 10.1101/854885 |
| Popis: | SummaryBrain 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. |
| Databáze: | OpenAIRE |
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