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Dissertation/Thesis Abstract

Melanoma-secreted Amyloid-Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
by Kleffman, Kevin, Ph.D., New York University, 2020, 187; 27667763
Abstract (Summary)

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. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain.

Here, we show that melanoma cells require amyloid beta (A), a polypeptide heavily implicated in Alzheimer’s disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete A, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of A decreases brain metastatic burden.

Our results reveal a mechanistic connection between brain metastasis and Alzheimer’s disease – two previously unrelated pathologies, establish A as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.

Indexing (document details)
Advisor: Hernando, Eva, Schneider, Robert
Commitee: Fisher, Edward A, Ghiso, Jorge, Mathews, Paul, Possemato, Richard, Boire, Adrienne
School: New York University
Department: Basic Medical Science
School Location: United States -- New York
Source: DAI-B 81/10(E), Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology
Keywords: Alzheimer's, Amyloid, APP, Brain Metastasis, Melanoma, Neurodegeneration
Publication Number: 27667763
ISBN: 9798607310424
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