American Association for Cancer Research
cd-21-1006_supplementary_figure_s3_suppsf3.pdf (10.78 MB)

Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

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journal contribution
posted on 2023-04-04, 00:03 authored by Kevin Kleffman, Grace Levinson, Indigo V.L. Rose, Lili M. Blumenberg, Sorin A.A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von Itter, Alfredo Floristán, Gillian Baptiste, Nicole M. Eskow, James A. Tranos, Jenny Chen, Eleazar C. Vega y Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue-Ming Li, Paul Mathews, Ronald B. DeMattos, Beatrix Ueberheide, Kelly V. Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando
Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis



NIH Melanoma SPORE


NYU Grossman School of Medicine

Experimental Pathology Core Facility




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. 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

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