Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis Journal Article
| Authors: | Kleffman, K.; Levinson, G.; Rose, I. V. L.; Blumenberg, L. M.; Shadaloey, S. A. A.; Dhabaria, A.; Wong, E.; Galán-Echevarría, F.; Karz, A.; Argibay, D.; Von Itter, R.; Floristán, A.; Baptiste, G.; Eskow, N. M.; Tranos, J. A.; Chen, J.; Vega y Saenz de Miera, E. C.; Call, M.; Rogers, R.; Jour, G.; Wadghiri, Y. Z.; Osman, I.; Li, Y. M.; Mathews, P.; DeMattos, R. B.; Ueberheide, B.; Ruggles, K. V.; Liddelow, S. A.; Schneider, R. J.; Hernando, E. |
| Article Title: | Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis |
| 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. © 2022 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; cancer survival; controlled study; human tissue; protein expression; human cell; genetics; nonhuman; nuclear magnetic resonance imaging; brain tumor; brain neoplasms; binding affinity; cell proliferation; mass spectrometry; mouse; metabolism; animal tissue; melanoma; metastasis; apoptosis; gene expression; confocal microscopy; image analysis; tumor volume; animal experiment; animal model; astrocyte; immunofluorescence; proteomics; enzyme linked immunosorbent assay; amino acid sequence; genetic transfection; cell culture; western blotting; brain metastasis; neoplasm metastasis; melanoma cell; immunoblotting; real time polymerase chain reaction; gene silencing; phagocytosis; tubulin; oxygen consumption; oxidative phosphorylation; alzheimer disease; cd45ra antigen; astrocytes; rna sequence; secretase; nerve degeneration; metabolic activation; parenchyma; rna analysis; beta actin; transmission electron microscopy; amyloid beta protein; rna isolation; nervous system inflammation; liquid chromatography-mass spectrometry; choroid plexus; machine learning; amyloid beta-peptides; tumor spheroid; astrocytosis; disease burden; humans; human; article; lentivirus infection; gene editing; crispr-cas9 system; hek293t cell line; brain to body luminescence ratio; tmt labeling; neuroinflammatory diseases |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-05-01 |
| Start Page: | 1314 |
| End Page: | 1335 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-1006 |
| PUBMED: | 35262173 |
| PROVIDER: | scopus |
| PMCID: | PMC9069488 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work