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Specifically packaged DNA secreted by tumor cells can set off an immune response that inhibits the metastatic unfold of the tumor to the liver, in response to a examine led by researchers at Weill Cornell Medication, Memorial Sloan Kettering Most cancers Middle and Korea’s Yonsei College. The invention improves the scientific understanding of most cancers development and anticancer immunity, and will yield new scientific instruments for assessing and lowering metastasis threat.
Within the examine, reported Dec. 3 in Nature Most cancers, the researchers examined most cancers cells’ secretion of brief stretches of DNA packaged on tiny capsules known as extracellular vesicles (EVs). All cells use EVs to secrete proteins, DNA and different molecules, and tumor cells are notably energetic EV secreters.
The organic features of those EV-packaged molecules are nonetheless being explored, however on this case, the researchers found that in numerous most cancers sorts, EV-DNA secreted by tumor cells works as a “danger” sign that prompts an anti-tumor response within the liver, lowering the chance of liver metastasis.
“Initially we hypothesized that more tumor EV-DNA would mean a worse prognosis, but we were surprised to find the opposite,” mentioned examine co-senior creator Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of Pediatrics and of Cell and Developmental Biology at Weill Cornell Medication.
The opposite co-senior authors of the examine are Dr. Han Sang Kim, affiliate professor at Yonsei College Faculty of Medication and a visiting affiliate professor of Molecular Biology Analysis in Pediatrics at Weill Cornell Medication; and Drs. Yael David and Jacqueline Bromberg of Memorial Sloan Kettering Most cancers Middle. The primary creator of the examine is Dr. Inbal Wortzel, a analysis affiliate within the Lyden laboratory.
Dr. Lyden and colleagues have present in prior analysis that tumor cells secrete snippets of EV-DNA from throughout their genomes, together with items with cancer-associated mutations. Within the new examine, they took a extra complete take a look at tumor EV-DNA, and in early experiments discovered one thing surprising.
“We had assumed that this DNA is in the form of ‘naked’ strands inside EVs, but we were surprised to find that it is mostly on the EV surface, wrapped around support proteins called histones, much as it would be in a chromosome,” mentioned Dr. Wortzel.
With the assistance of Dr. David’s lab, the researchers decided that these histone proteins have a singular set of modifications, hinting that EV-DNA has a selected signaling operate.
The workforce additionally recognized a number of genes that assist regulate EV-DNA packaging, and located that when one in every of these, APAF1, was absent, the quantity of EV-DNA secreted by tumor cells was sharply lowered.
Different latest work by Dr. Lyden and colleagues have proven that most cancers cells can secrete EV-packaged proteins and fatty acids that make the liver extra hospitable for metastatic tumor improvement. The workforce due to this fact suspected that tumor-secreted EV-DNA would additionally promote metastasis.
Nonetheless, in animal fashions of pancreatic and colorectal most cancers, boosting tumor EV-DNA ranges lowered metastasis threat—whereas lowering tumor EV-DNA ranges via genetic deletion of APAF1 drastically raised that threat.
“We also found that in colorectal cancer patients, those with low levels of EV-DNA in their tumors at the time of diagnosis were more likely to develop liver metastases later on, compared to those with high EV-DNA levels,” Dr. Kim mentioned.
The researchers found that tumor EV-DNA is taken up by liver-resident immune cells known as Kupffer cells, that are spurred by marks of injury within the EV-DNA to arrange immune cell clusters that resist liver metastases.
“This is a tumor suppressor mechanism that had not been described before, and we think the cancers that can turn it off, by secreting less EV-DNA, have a better chance of spreading,” Dr. Wortzel mentioned.
The researchers now hope to develop an EV-DNA-based prognostic check for metastasis threat, in addition to a vaccine-like remedy to boost tumor EV-DNA signaling and suppress metastasis in sufferers with early stage most cancers.
Extra info:
Nature Most cancers (2024).
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Weill Cornell Medical Faculty
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DNA secreted by tumor cell extracellular vesicles prompts anti-metastatic immune response (2024, December 3)
retrieved 3 December 2024
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