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 with those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacologic inhibition of Aβ decreases brain metastatic burden. Significance: Our results reveal a novel 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. This article is highlighted in the In This Issue feature, p. 1171

OBJECTIVES: To report cases of primary neuroendocrine tumours (NETs) of the kidney, including carcinoid tumour, large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC), which show a wide range of NE differentiation and biological behaviour, and are exceedingly rare. PATIENTS AND METHODS: The clinicopathological features of all nine renal NETs diagnosed during a 7‐year period were reviewed. RESULTS: Six carcinoids, two SCC and one LCNEC were identified from 2780 kidney tumours. No patient had carcinoid syndrome or other NE symptoms. Three of six carcinoids and no SCC/LCNEC arose in horseshoe kidneys. The mean size of the six carcinoids and three SCC/LCNEC was 4.8 cm and 12.2 cm, respectively. No carcinoid had tumour necrosis or mitosis. By contrast, three SCC/LCNEC had extensive tumour necrosis and brisk mitosis. All renal NETs were positive for synaptophysin but were variably positive for chromogranin and CD56. Three of six carcinoid tumours were confined to the kidney, and four of five patients were disease‐free at a mean (range) of 26 (6–74) months. One patient with nodal metastases has had no recurrence and another died with liver metastases. Three patients with SCC/LCNEC each presented with locally advanced disease and extensive lymphadenopathy; two of them died from distant metastasis or local tumour progression, and the third is currently alive with disease. CONCLUSIONS: Various NETs can occur in the kidney, but rarely. Renal carcinoids have a variable clinical course; SCC and LCNEC are associated with poor clinical outcomes. The diagnosis of NETs, especially LCNEC, requires awareness of their rare occurrence and prudent use of immunohistochemical NE markers.