Integrative Systemic and Local Metabolomics with Impact on Survival in High-Grade Serous Ovarian Cancer

Abstract

Cancer metabolism is characterized by alterations including aerobic glycolysis, oxidative phosphorylation, and need of fuels and building blocks. Targeted metabolomics of preoperative and follow-up sera, ascites, and tumor tissues, RNA sequencing of isolated tumor cells, local and systemic chemokine, and local immune cell infiltration data from up to 65 high-grade serous ovarian cancer patients and 62 healthy controls were correlated to overall survival and integrated in a Systems Medicine manner. Forty-three mainly (poly)unsaturated glycerophospholipids and four essential amino acids (citrulline) were significantly reduced in patients with short compared with long survival and healthy controls. The glycerophospholipid fingerprint is identical to the fingerprint from isolated (very) low-density lipoproteins (vLDL), indicating that the source of glycerophospholipids consumed by tumors is (v)LDL. A glycerophospholipid-score (HR, 0.46; = 0.007) and a 100-gene signature (HR, 0.65; = 0.004) confirmed the independent impact on survival in training ( = 65) and validation ( = 165) cohorts. High concentrations of LDLs and glycerophospholipids were independently predictors for favorable survival. Patients with low glycerophospholipids presented with more systemic inflammation (C-reactive protein and fibrinogen negatively and albumin positively correlated) but less adaptive immune cell tumor infiltration (lower tumor and immune cell PD-L1 expression), less oxygenic respiration and increased triglyceride biosynthesis in tumor cells, and lower histone expressions, correlating with higher numbers of expressed genes and more transcriptional noise, a putative neo-pluripotent tumor cell phenotype. Low serum phospholipids and essential amino acids are correlated with worse outcome in ovarian cancer, accompanied by a specific tumor cell phenotype. .

Neutrophil extracellular trap formation correlates with improved overall survival in ovarian cancer

“…This approach supports the analysis of pathomechanisms and related adaptative responses such as inflammation in great detail [7,8]. With regard to high grade serous ovarian cancer (HGSOC), it allowed us to identify predictive marker profiles [9] as well as novel drug targets [10]. A distinct role of the immune system in ovarian cancer affecting the kind of tumor spread of ovarian cancer was described by us already previously [11].…”

“…Evidence for activated neutrophils in ascites of non-miliary type of tumor spread. Ascites samples were obtained from 18 patients as described previously [9] and classified according to macroscopic features upon surgery into miliary (11 patients) and non-miliary (7 patients). Figure 1A indicates proteins caracteristic for NETs according to Brinkmann et al [20] which were found up-regulated in non-miliary ascites samples (Table S1).…”

Absence of PD-L1 on tumor cells is associated with reduced MHC I expression and PD-L1 expression increases in recurrent serous ovarian cancer

“…In a previous study20 we showed that especially (poly)unsaturated glycerophospholipids in serum were associated positively with (i) favorable survival, (ii) corresponding concentrations in ascites and tumor tissues, (iii) respiratory chain gene expressions, and (iv) histones expressions and negatively (v) with systemic inflammation and vi) fatty acid neosynthesis. Most striking was the positive correlation with the expression of many of the histones genes, which were themselves significantly positively correlated to the number of expressed genes and transcriptional noise.…”

“…All–except the two latter biogenic amines–were positively correlated. Interestingly, these metabolites were highly overlapping (37 out of 65 significantly associated metabolites overlapped with the 54 significantly with OS associated metabolites from the OS metabolomics study20, p = 3.6 10 −9 , Suppl. Fig.…”

Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma

“…Metabolomics, a noninvasive diagnostic technology that focuses on the metabolite profiles involved in disease perturbations and provides a characteristic fingerprint in disease, has been applied to clinical studies of many diseases, including different cancers . It is regarded to be a sensitive, accurate and high‐throughput platform for cancer diagnosis, prognostic evaluation and clinical trials, and ultra‐high performance liquid chromatography quadrupole time‐of‐flight mass spectrometry (UPLC‐Q‐TOF/MS) technology has been widely used for metabolite profiling in various clinical samples (eg, in serum and urine).…”