Cancer cells are known to spread genetic chaos. As cancer cells divide, DNA fragments and even whole chromosomes can be duplicated, translocated or completely lost. This is called chromosomal instability, and scientists at Memorial Sloan Kettering have found it to be linked to cancer invasion. The more unstable the chromosomes, the more likely they are to extract pieces of DNA from those chromosomes where they do not belong: outside the center of a cell nucleus and floating in the cytoplasm.
Cells interpret these false pieces of DNA as evidence of viral invaders, which shut off their internal warning bells and lead to inflammation. Immune cells travel to the site of the tumor and release protective chemicals. It’s a mystery why this immune response, triggered by the cancer cells, doesn’t spell out the reduction.
The elephant in the room is that we didn’t really understand how cancer cells could survive and thrive in this skeletal environment. “
Samuel Bakhoum, Physician, MSK and Member of the Human Oncology and Pathogenesis Program
According to a new study from Dr. Bakhoum’s laboratory published on December 28 in the journal Find cancer, the cause must be done, in part, by a molecule sitting outside the cancer cells that destroys the warning signals before they ever reach a neighbor ‘s immune cells.
The findings help explain why some tumors do not respond to immunotherapy, and – just as importantly – suggest methods applied to immunotherapy.
Finding dangerous DNA
The Dr. alarm system is called cGAS-STING. Bakhoum. When DNA from a virus (or unstable cancer chromosome) lands in a cell cytoplasm, cGAS binds to it, forming a molecule containing cGAMP, which is a warning sign. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral invader.
In addition, much of the cGAMP also travels outside the cell where it is a warning signal for neighboring immune cells. It activates their STING pathway and triggers a protective attack against the cell with oral infection.
Previous work from Bakhoum’s laboratory has shown that cGAS-STING signals within cancer cells cause them to assume features of immune cells – in particular, their ability to creep and migrate – which helps their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process. The new research shows how cancer cells respond to the warning signals that active cGAS-STING releases into the environment. Scissors-like proteins shake the signals, providing a second way in which the cells can block the threat of immune destruction.
Examples of human trigeminal breast cancer staining negative (left) and positive (right) for ENPP1 expression. Examples of human triple breast cancer staining negative (left) and positive (right) for ENPP1.
The scissors-like protein that cooks cancer cells is called ENPP1. When cGAMP finds its pathway outside the cell, ENPP1 binds it up and prevents the signal from reaching immune cells. At the same time, this cleavage releases an immune molecule called adenosine, which also eliminates inflammation.
Through a battery of tests performed in mouse models of breast, lung, and colorectal cancers, Dr. Bakhoum and his colleagues showed that ENPP1 acts as a control modifier for immune suppression and metastasis. Inversion inhibits immune responses and increases metastasis; deactivation enables immune responses and reduces metastasis.
The scientists also looked at ENPP1 in samples of human cancers. ENPP1 expression was associated with both increased metastasis and resistance to immunotherapy.
Empowering immunotherapy
From a treatment perspective, perhaps the most notable finding in the study is that converting the ENPP1 version could increase the sensitivity of several different types of cancer to immunotherapy drugs called checkers. The researchers showed that this approach was effective in mouse models of cancer.
Several companies – including one founded by Dr. Bakhoum and colleagues – are 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 as this makes it an easier target for drugs designed to prevent it.
It’s also pretty special. Since most other glands in a healthy person are not inflamed, drugs that target ENPP1 specifically affect cancer.
Finally, targeting ENPP1 weakens cancer in two different ways: “You simultaneously increase cGAMP levels outside the cancer cells, which activate STING in neighboring immune cells, while also inhibiting the production of the immune adenosine. strikes two birds with one stone, “Dr. Bakhoum explains.
The pace of the investigation has been very fast, he said. “One of the things I would be proud of if this research ends is helping patients soon, as we only started this work in 2018.”
He hopes to have a phase I clinical trial of ENPP1 inhibitors within a year.
Source:
Sloan Kettering Cancer Memory Center
Magazine Reference:
Li, J., et al. (2020) Metastasis and immune suppression from extracellular cGAMP hydrolysis. Find cancer. doi.org/10.1158/2159-8290.CD-20-0387.