Matthias Mann

A Proteogenomic View of Synchronous Endometrioid Endometrial and Ovarian Cancer

Abstract Purpose: Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histologic markers to distinguish SEOCs from single-site tumors. Experimental Design: We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, and Tübingen). For direct comparison with single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrioid endometrial cancer (EEC). For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry–based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes. Results: DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors. Conclusions: The integrated proteogenomic data show that SEOCs are distinguishable from endometrioid endometrial or endometrioid ovarian cancer. Based on their proteogenomic similarity to EECs, we conclude that most SEOCs represent primary EECs that have metastasized to the ovary.

NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

Tumors are surrounded by supportive cells called cancer-associated fibroblasts (CAFs), which normally help protect the tumor from the immune system. The researchers found that an enzyme in these fibroblasts, called NNMT, is a key driver of this protection: it triggers the release of immune-suppressing molecules that recruit "suppressor" immune cells to shield the tumor from attack, particularly in high-grade serous ovarian cancer, the most common and deadly form of ovarian cancer.