A recent discovery about the process of evasion by cancer cells has led researchers to a new approach to treat the disease.
Cancer cells are known to spread genetic chaos. As cancer cells divide, DNA segments and even entire chromosomes can be duplicated, mutated, or completely lost. This is called chromosomal instability, and scientists at Memorial Sloan Catering have learned that it is associated with cancer aggression.
The more volatile the chromosomes are, the more likely these chromosomes will end up with bits of DNA where they are not: floating outside the cell’s central nucleus and floating in the cytoplasm.
The cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells visit the site of the tumor and churn out protective chemicals. One mystery is why this immune response triggered by cancer cells does not prevent their collapse.
“The elephant in the room is that we didn’t really understand how the cancer cells were able to survive and grow in this inflammatory environment,” said Samuel Bakhoum, a physician-scientist at MSK and a member of the Human Oncology and Pathogenesis Program.
Dr. in Cancer Discovery magazine. The reason, according to a new study by Bakhoum’s lab, is that with a molecule sitting outside the cancer cells, which destroy the warning signals before they reach neighboring immune cells.
The findings help explain why some tumors do not respond to immunotherapy, and – equally important – suggest ways to sensitize them to immunotherapy.
Dangerous DNA detection
Warning system dr. The Bakhoum study is called cGAS-STING. When DNA is released from the virus (or unstable cancer chromosome) into the cytoplasm of a cell, cGAS binds to it, forming a compound molecule called cGAMP, which acts as a warning signal. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral attacker.
In addition, the majority of cGAMP also goes outside the cell, where it serves as a warning signal for neighboring immune cells. This activates their STING pathway and unleashes an immune attack against the viral infected cell.
Previous work by Bakhom Lab showed that cGAS-STING signaling inside cancer cells causes them to adopt characteristics of immune cells – specifically, the ability to crawl and migrate – which aids their ability to metastasize. is. This provides part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process.
New research shows how cancer cells deal with warning signals that release active CGAS-sting into the environment. A scissor-like protein cuts signals, providing a second way cells can pose a risk of immune destruction.
The scissors-like protein that coats the cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 cleaves it and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also calms inflammation.
Through a battery of experiments conducted in a mouse model of breast, lung, and colorectal cancer, Drs. Bakhoum and his colleagues showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning this on suppresses immune responses and increases metastasis; Discontinuing it enables an immune response and reduces metastasis.
Scientists also observed ENPP1 in human cancer samples. ENPP1 expression correlates with both metastasis and increased resistance to immunotherapy.
From a treatment standpoint, perhaps the most notable conclusion of the study is that turning off the ENPP1 switch may increase the sensitivity of many different cancer types to immunotherapy drugs called checkpoint inhibitors. Researchers showed that this approach was effective in mouse models of cancer.
Many companies – including a dr. Includes the establishment of Bakhoum and colleagues – now developing drugs to inhibit ENPP1 on cancer cells.
Dr. Bakhoum says that it is fortunate that ENPP1 is located on the surface of cancer cells because it makes it an easy target for drugs designed to block it.
It is also relatively specific. Because most other tissues in a healthy person do not have inflammation, drugs targeting ENPP1 primarily affect cancer.
Finally, targeting ENPP1 locates cancer in two different ways: “You are simultaneously increasing cGAMP levels outside of cancer cells, which activates STING in neighboring immune cells, while you increase immune-suppressive adenosine. Are also stopping production. Therefore, you are killing two birds with one stone, “Dr. Bakhoum explains.
They say the pace of research has been incredibly fast. “One of the things I would really prou
(This story is published from a wire agency feed without textual modifications.)
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