Year: 2022
Type: 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. 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.
Source: Cancer Discovery
Authors: 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
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Vilcek Foundation, Memorial Sloan-Kettering Cancer Center, Cure Alzheimer's Fund, Blas Frangione Foundation, National Institutes of Health, School of Medicine, New York University, University of Texas MD Anderson Cancer Center, NYU Grossman School of Medicine, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health
Awards: G1527402254, G15585836, G1734361364, G2045757108, G2051006376, Sandy Recovery Ventana Medical Systems Discovery XT, G2665966410, G289723095, G2958098884, G3162655872, G3396996220, G3422572501, G3584301129, G3589890445, Medical Scientist Research Service Award, G4102770861, G4222884455, Role of circular RNA CDR1as in melanoma, G5461682904, G5790579924, G5946519234, G6148665131, NYU Melanoma SPORE, Investigating the Role of Mitochondrial Metabolism and Amyloid Precursor Peptide Processing in Melanoma Brain Metastasis, Training Program in Molecular Oncology and Immunology, Substrate Feedback Mechanism of gamma-Secretase, G8047817453, G9000003249, G9000035293, G9000056458, G9000059258, G9000117978, Cancer Center Support Grant
OpenAlex ID: W4220836552