Melanoma cells that spread and grow in the brain secrete amyloid beta—nearly three times as much as melanoma cells that spread to other parts of the body, a new study finds. Researchers show amyloid beta, a protein implicated in Alzheimer’s disease, activates surrounding astrocytes—star-shaped cells that nourish neurons—to create a conducive anti-inflammatory environment for melanoma cells to lay down their roots in the brain.
The authors demonstrate inhibiting amyloid beta through pharmacological agents decreases the spread of melanoma to the brain. The study indicates suppressing neuroinflammation is a key factor governing brain metastasis and establishes amyloid beta as a potential therapeutic target for brain metastasis.
The researchers conducted proteomic analysis on short-term cultures of melanoma recovered from brain metastases in patients and found proteins implicated in neurodegenerative pathologies are abnormally expressed in these cells compared to melanoma cells that spread to other parts of the body.
The findings were published on March 9, 2022, in the journal Cancer Discovery, in an article titled “Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.”
Spread of any type of cancer to the brain foreshadows devastating outcomes. Among common types of cancers, nearly 40% patients in advanced stages of melanoma, a form of skin cancer of pigment cells (melanocytes), develop brain metastasis.
“Historically, these [Stage IV melanoma] patients have been excluded from most major clinical trials. Though recent trial data has demonstrated some efficacy of immune checkpoint blockade against asymptomatic melanoma brain metastases, patients with symptomatic melanoma brain metastases were largely unresponsive. These patients, along with asymptomatic patients who do not respond to immunotherapy or develop resistance, represent an unmet clinical need and urgently need new therapeutic options,” said Eva Hernando, PhD, a professor in the department of pathology, assistant dean for research integration at NYU Langone Health, and senior author of the study.
Hernando added, “The molecular mechanisms underlying melanoma brain metastasis are poorly understood. We sought to investigate these mechanisms, with the hope that a better understanding of how melanoma survives and grows in the brain may reveal novel therapeutic strategies for this devastating disease.”
The team found amyloid beta secreted by melanoma cells curbs immune responses that would recognize and attack cancer cells. The researchers propose amyloid beta shifts brain immune cells into an immunosuppressed mode enabling cancer cells to evade immune attacks. The team also showed, administering the beta secretase inhibitor LY2886721 that reduces amyloid beta levels, decreased the size of brain melanoma metastases by about half in mouse models.
“Our study reveals an unexpected role for tumor-secreted amyloid beta in promoting the survival of melanoma brain metastases, and suggest a new way to counter it,” said Hernando. “Our findings suggest it may be possible to repurpose anti-amyloid beta agents —many of which have already been extensively and safely tested in humans in large clinical trials for Alzheimer’s disease—for the treatment of melanoma brain metastasis.”
“The field has already developed treatments that have been shown in clinical trials to potently and safely reduce amyloid beta levels, but that fail to counter Alzheimer’s disease for reasons unknown,” said Kevin Kleffman, an MD-PhD student in Hernando’s lab and first author of the study. “With this in mind, our team is already evaluating whether repurposed, tested anti-amyloid beta antibodies could prevent or reduce brain metastases in animal studies. Another next step is combining immunotherapies, including checkpoint inhibitors, and anti-amyloid beta therapies to ensure they can be used safely together.”
In the current study, the scientists refined standard protocols to capture a more accurate proteomic profile of brain melanoma metastases. For instance, the team grew cells recovered from human metastatic brain tumors in cultures for only a short time to keep them from changing too much from their original state. The authors then measured the proteins produced by the melanoma cells using a novel whole cell proteomics test.
“To our knowledge, our study is the first to employ this strategy in the brain metastasis field. The strategy of proteomic screening of short-term cultures—which no longer contain normal brain tissue—allowed us to be certain that differentially expressed proteins related to neurodegeneration in brain vs non-brain metastasis samples represent adaptations of melanoma cells instead of simply detection of brain proteins from non-melanoma brain tissue in the brain metastasis samples,” said Hernando.
Using 24 human brain and non-brain melanoma metastases grown in short term-cultures, the team showed melanoma cells from the brain produce proteins related to Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Hernando said, “We performed quantitative 3D immunofluorescence of individual melanoma-associated microglia and astrocytes. To our knowledge, this study is the first to do so in the brain metastasis field and allowed for specific conclusions about melanoma-associated astrocytes and microglia phenotypes to be established in vivo rather than inferred from an in vitro assay.”
Stemming from the current findings, Hernando and her team will be conducting further preclinical studies on amyloid beta including assays testing safety and efficacy of anti-beta amyloid agents in combination with immune checkpoint inhibitors in an immune competent model of melanoma brain metastasis. They will also be probing into mechanisms underlying links between neurodegeneration and brain metastasis and pathways through which melanoma-secreted amyloid beta creates anti-inflammatory niches.
Hernando said, “Investigating whether soluble amyloid beta also has an anti-inflammatory role in other contexts is intriguing. This includes other brain cancers, such as breast and lung brain metastasis and glioblastoma, as well as non-cancer brain contexts including neurodegenerative disorders, stroke, CNS infection, and autoimmune disorders.”
If future investigations reveal a widespread anti-inflammatory role of soluble beta amyloid, this study would have spurred new concepts on brain pathologies and therapeutics.
