Patients with melanoma develop brain metastasis at a higher rate than those with any other common cancer, with an estimated 40 to 50 percent of stage 4 melanomas spreading to the brain. A new study led by NYU Langone Health researchers implicates proteins better known for their roles in neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease in that metastasis.
The study, published in Cancer Discovery, demonstrated that amyloid beta (Aβ) is essential for the growth and survival of melanoma cells in brain parenchyma.
“This study reveals an unexpected role for tumor-secreted amyloid beta in promoting the survival of melanoma brain metastases, and also suggests a new way to counter it,” says Eva M. Hernando-Monge, PhD, who led the research team.
“This study reveals an unexpected role for tumor-secreted amyloid beta in promoting the survival of melanoma brain metastases, and also suggests a new way to counter it.”Eva M. Hernando-Monge, PhD
In addition to suggesting a key role played by Aβ in advancing metastasis, the team showed in a proof-of-principle demonstration that beta-secretase inhibitors (BACEi) initially developed for Alzheimer’s disease may hold promise in delaying and significantly reducing the growth of brain metastasis in melanoma.
“We are trying to repurpose small molecule inhibitors and antibodies that were originally developed to target Aβ,” she says. “It’s very exciting but still early days for testing it.”
A New Research Model
Previous models of brain metastasis had yielded inconsistent results in differential gene expression. Dr. Hernando-Monge’s research team used a more physiological model consisting of short-term cultures of metastatic melanoma cells resected during patient surgeries to better represent the heterogeneity of the initial tumors. The group then used a proteomics analysis to compare 12 brain metastases with 12 extracranial metastases, including some pairs that had been resected from the same patient.
Some of the proteins upregulated in metastatic melanoma are involved in mitochondrial metabolism and scavenging of reactive oxygen species, suggesting a means by which melanoma cells in the brain may tamp down oxidative stress. In addition, the researchers found a significant upregulation of amyloid precursor protein (APP) as well as multiple proteins involved in processing and cleaving APP into Aβ.
Dr. Hernando-Monge hypothesizes that melanoma cells arriving in the brain adopt neural-like features and secrete soluble Aβ. Surrounding astrocytes would normally warn of the new threat, prompting microglia to phagocytose the metastatic cells. But Aβ may temper that normal immune response and enlist the astrocytes in a noninflammatory role that promotes growth of melanoma cells instead.
The group is now testing BACEi or anti-Aβ antibodies alone and in combination with immunotherapy as a potential treatment for brain metastasis, Dr. Hernando-Monge says.
Linking an Epigenetic Regulator to Metastasis
A second study led by Dr. Hernando-Monge’s team and published in the journal Science Advances has helped clarify why some melanomas metastasize and others don’t, even after being fully resected. “Years later, in some patients, there will be a recurrence or even a distal metastasis,” she says. “But when we compare the stage 1 or 2 tumors that have recurred with those that have not recurred, we don’t see any genetic mutation that distinguishes them.”
For years, the lab has hypothesized that epigenetic mechanisms could be drivers of the metastatic behavior. Through a systematic meta-analysis and mini-screen for chromatin-regulating genes consistently altered in metastasis, the group identified a protein called plant homeodomain finger protein 8, or PHF8, that is upregulated in metastatic melanoma cells compared to primary cancer cells.
Silencing PHF8, a histone demethylase, via two separate mechanisms had no effect on cell proliferation, but consistently reduced cell invasion in an in vitro assay. In a mouse model, silencing PHF8 also yielded a reduction in metastasis.
To shine more light on the potential mechanism, the study in turn characterized how the pro-metastatic TGF-β pathway is regulated by PHF8. Since the epigenetic regulator shares homology with multiple members of the same family, targeting it with sufficient specificity may be difficult. Even so, Dr. Hernando-Monge says other techniques, such as targeting PHF8 for degradation by linking it to a ubiquitin ligase enzyme or targeting other proteins downstream of its regulatory activity, may yet allow the pathway to be targeted therapeutically.
“There is much more that this PHF8 story has yet to reveal,” she says.