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Melanoma-secreted amyloid beta likely curbs neuroinflammation, promotes brain metastases

Cancer Discovery
Reuters Health - 15/03/2022 - Amyloid beta, a protein that builds up in the brains of patients with Alzheimer's disease, was shown in preclinical studies to promote brain metastases in melanoma and ramp down immune responses.

In addition, a beta secretase inhibitor significantly reduced the amount of brain melanoma metastases in mice.

"We were surprised to find that proteins related to neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, were differentially expressed in melanoma cells, suggesting a mechanistic link between brain cancer and neurodegeneration," Dr. Kevin Kleffman of NYU Grossman School of Medicine in New York City told Reuters Health by email.

"The discovery suggests that there may be shared pathologic features of these seemingly unrelated devastating diseases," he said. "Further investigation into this connection may yield important insights about both."

As reported in Cancer Discovery, Dr. Kleffman and colleagues conducted a proteomics analysis of 24 human brain and non-brain cancer metastases grown in short-term cultures, and showed that proteins implicated in neurodegenerative diseases are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases.

They then showed that silencing the gene that codes for the amyloid precursor protein reduced cancer metastases in a mouse model.

Further experiments showed that melanoma cells require amyloid beta to grow and survive in the brain parenchyma. Melanoma-secreted amyloid beta activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype, and prevents microglia from clearing (phagocytosis) the peptide from the brain.

The team also treated mice with brain metastases with a beta-secretase inhibitor, which blocks amyloid beta production, and found that treated mice had significantly less brain metastases compared to untreated mice.

The authors write, "Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer's disease..., establish (amyloid beta) as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma."

Dr. Kleffman said, "It is particularly exciting that anti-amyloid beta antibodies have been extensively tested in humans in Alzheimer's phase 3 clinical trials and, despite lacking clear efficacy in Alzheimer's disease, are well tolerated at high doses for extended periods of time."

"While our results suggest anti-amyloid beta agents may be able to be repurposed for the treatment of melanoma brain metastasis in the future, more preclinical studies are needed before a clinical trial could be considered," he added. "Given our findings that amyloid beta acts as an anti-inflammatory mediator in melanoma brain metastasis, an exciting possibility is that anti-amyloid beta agents may act synergistically with immunotherapy."

Dr. Colt Egelston, assistant research professor at the Beckman Research Institute of City of Hope in Duarte, California, commented in an email to Reuters Health, "The excellent work presented in this study lays a foundation for understanding the mechanistic role of amyloid beta proteins in melanoma brain metastasis. The findings here are still largely restricted to preclinical murine models of induced metastases, although patient-derived cancer cells are used. How critical these findings are for driving brain metastasis in melanoma patients must still be validated with further biological studies of patient tissue samples."

"Further studies are needed to determine if proteomic or genomic screening can reveal upregulation of amyloid beta protein pathways in the extracranial metastases or primary tumors of melanoma patients," he added. "Connecting the clonal evolution of primary tumor cancer cells with the rise of metastatic cancer clones that take advantage of this amyloid beta protein pathway will be important toward the clinical prevention and treatment of melanoma brain metastases."

SOURCE: https://bit.ly/3KPM72q Cancer Discovery, online March 9, 2022.

By Marilynn Larkin

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