Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

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. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Ab) for growth and survival in the brain parenchyma. Melanoma-secreted Ab activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Ab decreases brain metastatic burden.脑转移（brain metastasis）是多种癌症患者发病与死亡的关键诱因，同时存在尚未被满足的临床需求。目前，介导癌细胞在脑实质（brain parenchyma）内转移性生长的分子机制仍未完全阐明。黑色素瘤（Melanoma）作为常见癌症类型中脑转移发生率最高的癌种，是研究癌细胞如何适应脑实质微环境的理想模型。我们针对黑色素瘤短期培养体系（short-term cultures）开展的无偏倚蛋白质组学分析（unbiased proteomics analysis）显示，与从颅外转移灶（extracranial metastases）分离得到的黑色素瘤细胞相比，从脑转移灶分离得到的黑色素瘤细胞中，与神经退行性病变相关的蛋白质呈现差异表达。我们的研究证实，黑色素瘤细胞在脑实质内的生长与存活依赖于β淀粉样蛋白（amyloid beta, Ab）。黑色素瘤分泌的Ab可将周围的星形胶质细胞（astrocytes）激活为促转移、抗炎表型，并抑制小胶质细胞（microglia）对黑色素瘤细胞的吞噬作用。最后，我们证实通过药物抑制（pharmacological inhibition）Ab可有效降低脑转移负荷（brain metastatic burden）。