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Cancer cells have learned to "poison"!

 Last Update: 2022-04-23
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Metastasis is one of the main causes of death in cancer patients [1]

Brain metastases develop in 40-75% of patients with stage IV melanoma

Although clinical trial results 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 of brain metastases [4-7 ]

immunity

Recently, a research team led by Professor Eva Hernando of New York University Langone Medical Center published research results in the journal Canecr Discovery

The research team Canecr Discovery led by Professor Eva Hernando of NYU Langone Medical Center

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.

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 preventing microglia from engulfing melanin Melanoma cells that enter the brain secrete amyloid beta (Aβ) in order to survive Phagocytosis of melanoma cells

Let the "number one suspect" of Alzheimer's disease serve his transfer, the melanoma trick is absolutely perfect!

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

BACE inhibitors that inhibit Aβ protein secretion can reduce brain metastases in melanoma BACE inhibitors that inhibit Aβ protein secretion can reduce brain metastases in melanoma

This is "the devil is one foot high and the road is one foot high"

▲Screenshot of the homepage of the paper

▲Screenshot of the thesis homepage ▲▲ ▲

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.

Brain metastases-derived tumor cells exhibit enhanced brain metastases

Proteomic analysis revealed that brain metastases tumor cells were enriched for proteins associated with neurodegenerative diseases (Alzheimer's, Parkinson's and Huntington's)

Tumor cell enrichment in brain metastases and 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

▲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 the α-secretase complex.

Brain metastases tumor cells overexpress a variety of enzymes that cleave amyloid precursor protein (APP) and reduce Aβ production-related enzymes significantly

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

More Aβ in short-term culture supernatants of brain metastases

▲ A, B: Brain metastatic melanoma cells highly express the enzyme that cleaves APP; F: Brain metastatic melanoma cells secrete higher levels of Aβ

▲ A, B: Brain metastases melanoma cells highly express enzymes that cut APP; F: Brain metastases 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

APP knockdown melanoma cells have reduced brain metastatic capacity, but extracranial metastatic capacity is not affected

▲ After knocking down APP, the tumor's brain metastases significantly decreased

▲ After knocking down APP, the tumor's ability to metastasize to the brain was significantly reduced ▲ ▲ ▲

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

Whether it is to replenish the wild-type APP gene or the mutant APP gene, it can restore the brain metastatic ability of melanoma cells.

▲ Replenishment experiments prove that Aβ is the form of APP to promote tumor brain metastasis

▲ Replenishment experiments prove that Aβ is a 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

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

Knockdown of APP had no effect on tumor cell arrest, extravasation and growth in blood vessels , but tumor cells lacking APP could not establish metastases in the brain parenchyma, but developed apoptotic blood vessels

▲ A: Timeline of melanoma brain metastases; B: APP knockdown tumors fail to establish metastases

▲ 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 effect on astrocyte function [9-11]
.
The Hernando team therefore hypothesized that Aβ promotes tumor cell colonization by affecting the function of astrocytes
.

Aβ has a significant effect on astrocyte function

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
.

Aβ secreted by tumor cells can promote the increase of tumor local astrocytes

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
.

Aβ inhibits multiple inflammatory signaling pathways in astrocytes Aβ inhibits multiple inflammatory signaling pathways in astrocytes

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
.

Aβ suppresses 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 decreased 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 phagocytosis marker CD68 was significantly decreased
.

⁺In the presence of Aβ, microglia expressed more anti-inflammatory mediator Arg-1, while the expression of the phagocytic marker CD68 was significantly decreased In the presence of Aβ, microglia expressed more anti-inflammatory mediators The 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

▲ In the presence of Aβ, the 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
.

Knockdown of APP significantly reduces tumor burden even in established brain metastases

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
.

Brain metastases are significantly reduced after β-secretase inhibitor (BACEi) inhibition of Aβ secretion

▲ Inhibition of Aβ production or secretion significantly reduces melanoma brain metastasis

▲ Inhibition of Aβ production or secretion significantly reduces melanoma brain metastases ▲ ▲ ▲

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
.

For the first time, Aβ was found to help melanoma brain metastases, linking melanoma brain metastases to Alzheimer's disease, and suggesting that Aβ may be a promising tumor therapy target
.

Over 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 in the new field of tumor treatment.
Battlefield comes into play
.

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