Skin cancer cells use Alzheimer’s protein to sabotage brain’s immune defences

 

Washington, United States A new study reveals that skin cancer cells thrive when they spread to the brain thanks to the protein amyloid beta, which is known to accumulate in Alzheimer's patients' brains.

The study, which was published online on March 9 in the journal Cancer Discovery, a publication of the American Association for Cancer Research, found that melanoma, the most fatal form of skin cancer, relies on amyloid beta to survive in the brain. Melanoma was the focus of the study because, out of all common cancers, it spreads (metastasizes) to the brain in 40% of patients with advanced (Stage IV) disease.

The study, which was led by researchers from the Laura and Isaac Perl mutter Cancer Center at NYU Grossman School of Medicine, found that metastatic melanoma cells recovered from human brains and grown in tissue cultures produce approximately three times as much amyloid beta as cancer cells that have spread elsewhere in the body.

Additionally, the researchers discovered that cancer cells secrete amyloid beta, which suppresses immune responses that would otherwise recognize cancer cells as abnormal and attack them in the same manner as they do to invade bacteria. 

The researchers hypothesize that amyloid beta causes immune cells in the brain to behave in a way that is similar to how infections go away and tissues start to heal, allowing cancer cells to go undetected. The team also demonstrated that the beta secrete inhibitor LY2886721, which is known to significantly lower levels of amyloid beta, reduced the size of brain melanoma metastases in study mice by about half.

Senior study author Eva Hernando, PhD, assistant dean for Research Integration at NYU Langone Health, says, "Our study reveals an unexpected role for tumor-secreted amyloid beta in promoting the survival of melanoma brain metastases and suggests a new way to counter it". 

The current discovery adds to the mystery surrounding amyloid beta, the primary component of deposits in Alzheimer's patients' brains. Hernando, who is also a member of Perl mutter Cancer, says that despite numerous studies, its roles in normal function and Alzheimer's disease remain contentious, even as new proposed roles emerge

Cancer Can’t Take Root

To begin, the research team grew human metastatic brain tumor cells in cultures for a brief period of time to prevent their genetic evolution to the point where they no longer resembled the original cancer cells. The researchers hypothesized, based on these data, that cancer cells make amyloid beta in the brain to help them survive.

They examined the effect of silencing the gene that codes for amyloid precursor protein (APP), a protein that is processed into amyloid beta by secrete enzymes (beta and gamma) in melanoma cells injected into the hearts of study mice, in order to test the hypothesis. 

According to imaging results, the number of brain cancer metastases significantly decreased when the APP gene was silenced, cutting off the cancer cells' supply of amyloid beta. Other experiments revealed that the immune attack prevented melanoma cells lacking amyloid beta from successfully growing (dividing and multiplying) at the stage when they are forming small cell colonies (micrometastases), which are necessary for cancer cells spreading to "take root" in a new tissue.

Lastly, the study found that astrocytes, brain cells that nourish neuron-carrying brain cells and release proteins that suppress immune responses to cancer, are affected by amyloid beta released by melanoma cells.

According to first study author Kevin K L-E F man, PhD, an MD-PhD student at NYU Langone and a member of Hernando's lab, "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 that are unknown".

In light of this, our team is currently assessing whether animal studies could reduce or prevent brain metastases using repurposed, tested anti-amyloid beta antibodies. Combining immunotherapies, such as checkpoint inhibitors, and anti-amyloid beta therapies to make sure they can be used safely together is another next step