A cell can be pictured like a social network: in theory, every person is connected to every other person in the world through surprisingly few degrees of separation. Cell factors in molecular networks are connected to each other in an analogous way. If one stops functioning correctly, the system is thrown out of balance. The result is a cascade of effects that can have wide-ranging and unexpected consequences on more distant parts of the network. Deciphering these cascades can contribute to scientists’ understanding of how a minor defect in a cell’s system can lead to diseases like cancer. These insights offer ideas for new treatments. Breast cancer is at center of active research due for its high mortality; when it spreads to other organs usually heralds a poorer prognosis.
Researchers at the University and University Hospital of Basel have discovered a process that helps breast cancer cells implant themselves in certain places in the body. The team led by Professor Mohamed Bentires-Alj worked to establish the role of a cellular enzyme in breast cancer metastasis, by discovering a mechanism that appears to support metastasis in a range of aggressive cancers. The team elucidated one of these cascades. It begins with a metabolic enzyme called nicotinamide N-methyltransferase, or NNMT for short. And it ends with the substance that fills the space between the body’s cells and holds them together: collagen. This proteins is good since it maintains a proper tissue folding. But in the case of metastatic cancer it helps cancer cells embed themselves in new tissues.
“Triple negative” breast cancer, which affects roughly 15 percent of all breast cancer patients, is particularly aggressive because it often spreads throughout the body and forms lung and brain metastases. These breast cancer cells express unusually high amounts of an enzyme called NNMT. As the researchers learned through experiments on animals, overproduction of NNMT is key to the metastasis. Why? The answer is found at the end of the cascade, with collagen. As the Basel research team reports, overproduction of NNMT causes the cancer cells to also produce more collagen than normal. It is known from previous studies that wandering cancer cells first have to find their way around in new tissues. The environment there is different from that of the original tumor.
In this preliminary stage of metastasis, the collagen in the new tissue helps the cancer cells survive and adapt. What the new study found: particularly aggressively metastasizing breast cancer cells not only produce an excessive amount of NNMT, but also their own collagen. When the researchers removed NNMT from aggressive breast cancer cells and injected these cells into mice, the animals developed hardly any metastases and the cells also produced hardly any collagen. Researchers investigated some molecular mechanisms behind this effect. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation and DNA methylation at the promoters of enzyme PRDM5 and extracellular matrix-related genes.
PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Beside, the enzyme NNMT produces more N-methyl-nicotinamide, which intracellularly is a competitive inhibitor of the nuclear family enzymes of poly-ADP-ribose polymerases (PARPs). These enzymes, particularly PARP1 and 2, are actively involved in chromatin remodeling and DNA repair, along with chromatin stability through interaction with partners like the tumor suppressor p53. Other mechanisms could mediate the effect of NNMT as well, as the one recently published in a research showing the participation of the signaling axis PP2A-ERK-AP1-ABCA1. A literature review also found that overproduction of NNMT is typical of a whole range of aggressive cancers.
This means that beside breast cancers, other lethal types like pancreatic, lung or stomach cancer coud take advantage of this discovery. And that NNMT could be deemed as an universal and potential metastasis target to disable.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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