High-grade serous carcinomas (HGSC) make up the majority of ovarian cancer cases. Unfortunately, they have the lowest survival rates. HGSC is a tumor type that occurs primarily in the ovaries and spreads throughout the abdominal cavity. Most patients are diagnosed with late-stage disease that has already spread. Until recently, therapy has been limited to surgery and traditional chemotherapeutic agents. A systematic examination of the tumor and surrounding tissue — particularly normal cells called fibroblasts — has revealed a new treatment target that could potentially prevent the rapid dissemination and poor prognosis associated with high-grade serous carcinoma.
In close collaboration with Fabian Coscia and Matthias Mann, from the Max Planck Institute of Biochemistry in Munich and University of Copenhagen, researchers profiled the expression of more than 5,000 proteins in both normal and cancerous tissues derived from minute amounts of patient biobank material. “When we then got our first data, we were fascinated to find that the metastatic stroma was characterized by a highly conserved protein signature, as opposed to the cancer cells”, adds Fabian Coscia, postdoctoral researcher in Matthias Mann’s group and one of the two first-authors of the study. As these metastatic changes were seen in all of their analyzed patients, the team then went on to understand its functional role during metastasis with the ultimate goal to find novel therapeutic targets.
Indeed, they discovered a metabolic enzyme, nicotinamide N-methyltransferase (NNMT), highly expressed in the stroma surrounding metastatic cancer cells. The researchers found that NNMT causes widespread gene expression changes in the tumor stroma, converting normal fibroblasts to cancer-associated fibroblasts that support and accelerate tumor growth. Stromal NNMT expression encouraged ovarian cancer migration, proliferation, growth and metastasis. It was associated with poor clinical outcomes in patients.
They also found that inhibition of NNMT activity may be able to reduce or even reverse many of the tumor-promoting effects of cancer-associated fibroblasts. This suggests, they note, that the stroma should be explored as a new treatment target. Coscia, co-first author on the manuscript who led the proteomics analysis, added that “this method may be used to discover other proteins that are important for metastasis and to identify early changes during disease development.”
“When we put it all together,” Lengyel added, “it gave us exciting results. We have linked high-end technology including proteomics and metabolomics to functional analysis to improve our understanding of the stroma."