Skin Cancer Cells Depend on Alzheimer’s Protein To “Take Root” in the Brain
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Researchers from NYU Grossman School of Medicine have discovered that skin cancer (melanoma) cells rely on amyloid beta (Aβ) to survive and thrive once they have metastasized to the brain. The team found that the cancer cells retrieved from human brains and grown in tissue cultures secreted approximately three times as much Aβ as cancer cells that had metastasized to other sites within the body. It appears that the release of Aβ triggers surrounding astrocytes (specialized glial cells) to adopt a prometastatic, anti-inflammatory phenotype and also prevents phagocytosis of cancer cells by a specialized population of macrophage-like cells called microglia. The findings were published in Cancer Discovery.
What is amyloid beta?
Amyloid beta (Aβ) is a peptide derived from amyloid precursor protein (APP). A build-up of Aβ in specific regions of the brain has been identified as a pathological hallmark of Alzheimer's disease. The aggregated protein forms plaques that disrupt and destroy neurons resulting in progressive cognitive impairment that is characteristic of the disease.
Technology Networks spoke with the study’s corresponding author Dr. Eva Hernando-Monge, professor in the department of pathology and assistant dean for research integration at NYU Grossman School of Medicine, to learn more about the research.
Laura Lansdowne (LL): You demonstrated, in a study using mice, that the beta-secretase inhibitor LY2886721 decreased the size of brain metastases by approximately 50%. Can you tell us more about this therapeutic approach and the design of the preclinical study?
Eva Hernando (EH): This compound suppresses the production of amyloid beta (Aβ) by inhibiting the enzyme that cleaves the precursor (APP) into smaller pieces, one of which is Aβ. In the preclinical models used in this study, we first induce melanoma brain metastasis in mice by injecting human melanoma cells in their hearts, which allows cancer cell dissemination into various organs including the brain. Then we start to feed the mice with food containing the inhibitor mentioned above. We monitored the mice for metastatic burden over time, and at termination of the experiment. We observed that the mice treated with the beta-secretase inhibitors had smaller brain metastasis and fewer metastases than those treated with control food.
LL: Do you plan to conduct further testing? If so, could you tell us more?
EH: We are following these two lines of research:
- We are testing alternative approaches to targeting Aβ using preclinical models. In particular, we are starting to test anti-Aβ antibodies that have been used previously in clinical trials with Alzheimer’s patients (and although they didn't show cognitive improvement in patients, they showed on-target activity without toxicity). The beta-secretase inhibitor not only impacts Aβ levels, but also other proteins also cleaved by beta-secretase. Therefore, using an anti-Aβ antibody may be a more direct and specific, as well as less toxic means to target Aβ.
- We are examining the effects of targeting Aβ beyond xenograft models, moving into “syngeneic” models (murine melanoma cells injected into mice with a complete immune system). If Aβ suppression has the same effect in those modes, we will then test inhibitors or antibodies targeting Aβ alone, or in combination with immunotherapies that are approved and used for the treatment of metastatic melanoma.
LL: What “new techniques” did you use to uncover the connection between brain cancer and neurodegenerative disease?
EH: We performed unbiased mass spectrometry-based proteomics analysis of whole-cell lysates from a cohort of 24 melanoma short-term cultures, which are melanoma patient samples adapted to grow in a dish and kept at low passage number. To our knowledge, our study is the first to employ this strategy in the brain metastasis field. Importantly, 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.
Additionally, we performed quantitative 3D immunofluorescence of individual melanoma-associated microglia and astrocytes. To our knowledge, this study is the first of its sort 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.
LL: Could other cancers that are known to metastasize to the brain exploit amyloid beta in this way? If so, do you plan to study this?
EH: It is possible, but we haven't demonstrated that yet. We are currently investigating that possibility.
Reference: Kleffman K, Levinson G, Rose IVL, et al. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis. Cancer Discovery. 2022;12(5):1314-1335. doi: 10.1158/2159-8290.CD-21-1006
Dr. Eva Hernando was speaking to Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.