First time discovered: Melanoma cells secrete Alzheimer’s disease “toxic protein”
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First time discovered: Melanoma cells secrete Alzheimer’s disease “toxic protein”.
Cancer cells have learned to “poison”! Scientists discover for the first time that melanoma cells secrete Alzheimer’s disease “toxic protein”, which enables astrocytes to promote cancer metastasis and inhibit the phagocytosis of microglia
Metastasis is one of the main causes of death in cancer patients [1]. Different tumors have different metastatic preferences, and 40-75% of patients with stage IV melanoma will develop brain metastases [2,3] .
Although clinical trials have shown that melanoma brain metastases still respond to approved targeted therapies and immunotherapy, the duration of this response is short, and most patients eventually die from brain metastases [4-7 ] . Therefore, we urgently need to understand the mechanism of melanoma brain metastases and provide new therapeutic strategies for patients with brain metastases.
Recently, a research team led by Professor Eva Hernando of New York University Langone Medical Center published research results in the journal Canecr Discovery [8] .
They found that in order to survive, melanoma cells entering the brain secrete beta-amyloid (Aβ) proteins that recruit and promote the transformation of astrocytes into a cancer-promoting phenotype, while also preventing microglia. Phagocytosis of melanoma cells .
Let the “number one suspect” of causing Alzheimer’s disease serve his transfer, the melanoma is really a trick!
However, melanoma cells may not have thought that the Aβ inhibitor that has been used in clinical research is waiting for it! Hernando’s team found that BACE inhibitors that inhibit Aβ protein secretion can reduce melanoma brain metastases .
▲ Screenshot of the homepage of the paper
To find the characteristics of brain metastases, Hernando’s team isolated tumor cells from brain metastases (BM) and non-brain metastases (NBM) of the same melanoma patient, and then used short-term cultures (STC) for short-term culture. Mouse tumor-bearing experiments, and unbiased proteomic analysis. Tumor-bearing experiments in mice showed that tumor cells derived from brain metastases exhibited stronger brain metastases . This suggests that cells in brain metastases have a unique ability to better adapt to the environment within the brain.
Proteomic analysis revealed that brain metastases tumor cells were enriched for proteins associated with neurodegenerative diseases (Alzheimer’s, Parkinson’s and Huntington’s) .
▲ A: Schematic diagram of specimen acquisition; BD: BM-SCT has stronger ability of brain metastases; E: BM-SCT upregulates various pathways related to neurodegenerative diseases
Further investigation of differentially expressed proteins by Hernando’s team found that tumor cells in brain metastases highly expressed a variety of enzymes that cleave amyloid precursor protein (APP) , such as α-secretase (BACE2) and the catalytic subunit of α-secretase complex. basal (PSEN1); while enzymes associated with reducing Aβ production , such as the ubiquitin ligase UCHL1 and ADAM19, were significantly reduced .
So can melanoma cells secrete Aβ? Hernando’s team examined the levels of Aβ in the supernatant of melanoma cell cultures, and the results showed that there was more Aβ in the supernatant of short-term cultures of brain metastases . Given the effects Aβ can have on the brain, they hypothesized that melanoma cells might need Aβ to help them survive and grow in the brain parenchyma.
▲ A, B: Brain metastatic melanoma cells highly express the enzyme that cuts APP; F: Brain metastatic melanoma cells secrete higher levels of Aβ
So can Aβ really affect the ability of melanoma cells to metastasize to the brain? Hernando’s team knocked down APP in melanoma cells and found that the ability of melanoma cells to knock down APP decreased brain metastasis, but the extracranial metastasis ability was not affected . These results suggest that APP is required for the colonization of melanoma cells in the brain.
▲ After knocking down APP, the tumor’s brain metastases significantly decreased
As we all know, APP is the precursor of Aβ, and it has various processing forms, so which form does APP play a role in? Combining the aforementioned findings, Hernando’s team hypothesized that Aβ is the form in which APP functions.
In order to test this conjecture, they conducted backfilling experiments. A mutant APP gene—SPA4CT-T43P—was introduced into melanoma cells in which the APP gene had been knocked out—the mutant gene expressed mainly Aβ, rather than other processed forms of APP. The results showed that both the wild-type APP gene and the mutant APP gene could restore the brain metastatic ability of melanoma cells . This suggests that Aβ is the form of APP required for melanoma brain metastases .
▲ Replenishment experiments prove that Aβ is the form of APP to promote tumor brain metastasis
So what role does Aβ play in melanoma brain metastases? Hernando’s team first looked at the process of melanoma cells metastasizing into the brain, establishing a timeline of metastasis. We then compared the metastatic process of APP knockdown melanoma cells with wild-type (WT) melanoma cells.
The experimental results showed that knockdown of APP had no effect on tumor cells stasis, extravasation and growth in blood vessels, but tumor cells lacking APP could not establish metastases in the brain parenchyma, but underwent apoptosis . These data suggest that melanoma cells require Aβ to help colonize the brain parenchyma.
▲ A: Timeline of melanoma brain metastases; B: APP knockdown tumors fail to establish metastases
Why does Aβ have the ability to help melanoma cells colonize the brain? Existing studies have shown that astrocytes are an important regulator of tumor brain metastasis, and Aβ has a significant impact on astrocyte function [9-11]. The Hernando team therefore hypothesized that Aβ promotes tumor cell colonization by affecting the function of astrocytes.
They found from immunofluorescence results that astrocytes around tumor cells lacking APP were significantly reduced. This indicates that Aβ secreted by tumor cells can promote the increase of local astrocytes in the tumor .
How does Aβ affect the function of astrocytes? Hernando’s team used melanoma cell-conditioned medium to culture primary astrocytes and found that Aβ inhibited multiple inflammatory signaling pathways in astrocytes , especially the complement cascade pathway.
Using immunofluorescence, confocal microscopy, and three-dimensional imaging, Hernando’s team validated the sequencing results and found that the complement C3 protein, which is highly expressed in inflammatory astrocytes (A1), was reduced in the presence of Aβ. These data suggest that Aβ inhibits inflammatory A1 polarization of astrocytes and promotes tumor immune escape .
▲ C: The number of astrocytes around the brain metastases tumor cells was significantly reduced after knockdown of APP; F: The expression of C3 in astrocytes was significantly reduced in the presence of Aβ
Considering that C3 secreted by astrocytes can stimulate the polarization of microglia towards a pro-inflammatory phenotype and enhance their phagocytosis [12-14], Hernando’s team hypothesized that Aβ could inhibit the transformation of microglia into a pro-inflammatory phenotype. polarization and phagocytosis.
They observed the phenotype of melanoma-associated microglia (Iba1 + ) by immunofluorescence, confocal microscopy, and three-dimensional imaging, and found that in the presence of Aβ, microglia expressed more anti-inflammatory mediator Arg -1, while the expression of phagocytic function marker CD68 was significantly decreased .
These data suggest that Aβ can promote the anti-inflammatory phenotype polarization of microglia and protect melanoma cells from phagocytosis by microglia.
▲ In the presence of Aβ, microglia highly express the anti-inflammatory mediator Arg-1, and the phagocytic function decreases
Now that we know the important role of Aβ in melanoma brain metastases, can Aβ inhibition reduce melanoma brain metastases?
Hernando’s team knocked down the expression of APP in an established brain metastasis model through an inducible shRNA system. The experimental results showed that even in established brain metastases, knocking down APP could significantly reduce the tumor burden .
Subsequently, Hernando’s team treated tumor-bearing mice with a beta-secretase inhibitor (BACEi) , and could see a significant reduction in brain metastases after inhibiting Aβ secretion . These results suggest that inhibition of Aβ can effectively reduce melanoma brain metastases and inhibit tumor growth.
▲ Inhibition of Aβ production or secretion significantly reduces melanoma brain metastasis
Overall, this study is the first to find that Aβ can help melanoma brain metastases, link melanoma brain metastases to Alzheimer’s disease, and suggest that Aβ may be a promising tumor therapy target .
In the past few decades, scientists have developed numerous Aβ-clearing drugs, which can effectively clear Aβ in the brain. Although they have failed in preventing Alzheimer’s disease progression, they may be used in the future of tumor therapy. Battlefield comes into play.
references:
1. Seton-Rogers S. Metastases arrive at other organs via bone. Nat Rev Cancer. 2021;21(7):411. doi:10.1038/s41568-021-00370-0
2. Patel JK, Didolkar MS, Pickren JW, Moore RH. Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg 1978;135(6):807-10 doi 10.1016/0002-9610(78)90171-x.
3. de la Monte SM, Moore GW, Hutchins GM. Patterned distribution of metastases from malignant melanoma in humans. Cancer Res 1983;43(7):3427-33.
4. Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18(7):863-73 doi 10.1016/S1470-2045(17)30429-1.
5. Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018;379(8):722-30 doi 10.1056/NEJMoa1805453.
6. Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018;19(5):672-81 doi 10.1016/S1470-2045(18)30139-6.
7. Zhang D, Wang Z, Shang D, Yu J, Yuan S. Incidence and prognosis of brain metastases in cutaneous melanoma patients: a population-based study. Melanoma Res 2019;29(1):77-84 doi 10.1097/CMR.0000000000000538.
8. Kleffman K, Levinson G, Rose IVL, et al. Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis [published online ahead of print, 2022 Feb 24]. Cancer Discov. 2022;candisc.1006.2021. doi:10.1158/2159-8290.CD-21-1006.
9. Schwartz H, Blacher E, Amer M, Livneh N, Abramovitz L, Klein A, et al. Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation.Cancer Res 2016;76(15):4359-71 doi 10.1158/0008-5472.CAN-16-0485.
10. Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 2010;30(9):3326-38 doi 10.1523/JNEUROSCI.5098-09.2010.
11. Ye B, Shen H, Zhang J, Zhu YG, Ransom BR, Chen XC, et al. Dual pathways mediate beta-amyloid stimulated glutathione release from astrocytes. Glia 2015;63(12):2208-19 doi 10.1002/glia.22886.
12. Lian H, Litvinchuk A, Chiang AC, Aithmitti N, Jankowsky JL, Zheng H. Astrocyte Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer’s Disease. J Neurosci 2016;36(2):57789 doi 10.1523/JNEUROSCI.2117-15.2016.
13. Chen T, Lennon VA, Liu YU, Bosco DB, Li Y, Yi MH, et al. Astrocyte-microglia interaction drives evolving neuromyelitis optic lesion. J Clin Invest 2020;130(8):4025-38 doi 10.1172/JCI134816.
14. Wei Y, Chen T, Bosco DB, Xie M, Zheng J, Dheer A, et al. The complement C3C3aR pathway mediates microglia-astrocyte interaction following status epilepticus. Glia 2021;69(5):1155-69 doi 10.1002/glia.23955.
First time discovered: Melanoma cells secrete Alzheimer’s disease “toxic protein”
(source:internet, reference only)
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