American Association for Cancer Research
Browse
cd-21-1006_supplementary_video_2_suppsv2.avi (304.17 kB)

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

Download (304.17 kB)
media
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 Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Funding

NIH

NIH Melanoma SPORE

NCI

NYU Grossman School of Medicine

Experimental Pathology Core Facility

ORIP

History

ARTICLE ABSTRACT

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

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC