Scientists Discover Enzyme with Key Role in Aggressive Ovarian Cancers

Scientists discovered a metabolic enzyme that adds methyl groups to other molecules, called nicotinamide N-methyltransferase, that plays an important role in the progression of high-grade serous carcinoma, the most deadly form of ovarian cancer.

The findings of the study, “Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts,” were published in the journal Nature.

High-grade serous carcinoma (HGSC) is the most common type of ovarian cancer because of its ability to spread to other organs in the abdominal cavity early on.

For years, scientists have been studying the genetic and protein signatures of ovarian cancer cells in an effort to develop new ways to target and eliminate these cells. Recently, they came to the conclusion that a systematic approach focused not only on cancer cells, but also on the cells that support tumor growth (stromal cells), was required to stop cancer progression.

In this study, a group of researchers from the University of Chicago and their collaborators set out to characterize changes in protein levels occurring in cancer cells and in stromal cells during HGSC development.

They established a proteomic workflow to analyze changes in the levels of 6,944 proteins found in 107 tissue samples from the tumor itself and the surrounding stroma tissue.

Samples included tissues from the primary tumor and secondary metastases (other regions in the body where cancer has spread), as well as the surrounding tumor support tissues. All samples were obtained from 11 patients who had been diagnosed with HGSC.

They found the protein signature of ovarian cancer cells varied widely among patients, but remained relatively stable from the onset of HGSC up until the onset of cancer metastasis.

“Our results emphasize the molecular [variability] of ovarian cancer, and reveal that [all the proteins produced in a cell] within individual patients are relatively stable during progression — as was also recently observed in breast cancer,” the researchers stated.

However, they were surprised to find the protein signature of non-cancerous stromal cells surrounding tumor metastases was highly conserved among all patients during HGSC progression. In particular, they found that nicotinamide N-methyltransferase (NNMT), an enzyme that normally plays a key role in cell metabolism, was highly produced by stromal cells.

“For the first time, we were able to distinguish the molecular changes in the cancer cells from the ones happening in the adjacent stroma throughout disease progression,” Fabian Coscia, PhD, from the Max Planck Institute of Biochemistry in Munich and University of Copenhagen and co-first author of the study, said in a news release. “When we then got our data, we were fascinated to find that the metastatic stroma was characterized by a highly conserved protein signature, as opposed to the cancer cells.”

Remarkably, they discovered that the presence of high levels of NNMT in the stroma tissue triggered alterations in the genetic signature of normal fibroblasts (connective tissue samples) that became cancer-associated fibroblasts (CAFs). These CAFs are fibroblasts that produce and release molecules that support and accelerate the growth and expansion of cancer cells.

In addition, they found that inhibiting the activity of NNMT decreased, or even reversed, some of these effects, suggesting “that stromal methyltransferase activities can be targeted to normalize the metastatic stroma and should be further explored as treatment targets for cancer,” they said.

“When we put it all together, it gave us exciting results. We have linked high-end technology, including [study of proteins] and [study of molecules involved in metabolism], to improve our understanding of the stroma,” said Ernst Lengyel, MD, PhD, professor and chair of obstetrics and gynecology at the University of Chicago Medicine and corresponding author of the study.