Investigator
University Medical Center Hamburg Eppendorf
Glycan diversity in ovarian cancer: Unraveling the immune interplay and therapeutic prospects
AbstractOvarian cancer remains a formidable challenge in oncology due to its late-stage diagnosis and limited treatment options. Recent research has revealed the intricate interplay between glycan diversity and the immune microenvironment within ovarian tumors, shedding new light on potential therapeutic strategies. This review seeks to investigate the complex role of glycans in ovarian cancer and their impact on the immune response. Glycans, complex sugar molecules decorating cell surfaces and secreted proteins, have emerged as key regulators of immune surveillance in ovarian cancer. Aberrant glycosylation patterns can promote immune evasion by shielding tumor cells from immune recognition, enabling disease progression. Conversely, certain glycan structures can modulate the immune response, leading to either antitumor immunity or immune tolerance. Understanding the intricate relationship between glycan diversity and immune interactions in ovarian cancer holds promise for the development of innovative therapeutic approaches. Immunotherapies that target glycan-mediated immune evasion, such as glycan-based vaccines or checkpoint inhibitors, are under investigation. Additionally, glycan profiling may serve as a diagnostic tool for patient stratification and treatment selection. This review underscores the emerging importance of glycan diversity in ovarian cancer, emphasizing the potential for unraveling immune interplay and advancing tailored therapeutic prospects for this devastating disease.
BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer
Methylation of the BRCA1 promoter is an epigenetic gene expression regulator and is frequently observed in ovarian cancer; however, conversion of methylation status is thought to drive disease recurrence. Therefore, longitudinal monitoring of methylation status by liquid biopsy in cell‐free DNA may be a predictive marker. In total, 135 plasma samples were collected from 69 ovarian cancer patients before and during systemic treatment. Our liquid biopsy assay could detect down to a single molecule of methylated DNA in a high background of normal DNA (0.03%) with perfect specificity in control samples. We found that 60% of the cancer patients exhibited BRCA1 promoter hypermethylation at one point, although 24% lost hypermethylation during treatment. Multivariate survival analyses indicate that relapses are independent events and that hypermethylation and methylation conversion are independently correlated to longer relapse‐free survival. We present a highly sensitive and specific methylation‐specific quantitative PCR‐based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy‐resistant clones and unfavorable clinical outcome.
Molecular characteristics and tumorigenicity of ascites‐derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer
Ovarian cancer disseminates primarily intraperitoneally. Detached tumor cell aggregates (spheroids) from the primary tumor are regarded as ‘metastatic units’ that exhibit a low sensitivity to classical chemotherapy, probably due to their unique molecular characteristics. We have analyzed the cellular composition of ascites from OvCa patients, using flow cytometry, and studied their behavior in vitro and in vivo . We conclude that ascites‐derived cultured cells from OvCa patients give rise to two subpopulations: adherent cells and non‐adherent cells. Here, we found that the AD population includes mainly CD90 + cells with highly proliferative rates in vitro but no tumorigenic potential in vivo , whereas the NAD population contains principally tumor cell spheroids (EpCAM + /CD24 + ) with low proliferative potential in vitro . Enriched tumor cell spheroids from the ascites of high‐grade serous OvCA patients, obtained using cell strainers, were highly tumorigenic in vivo and their metastatic spread pattern precisely resembled the tumor dissemination pattern found in the corresponding patients. Comparative transcriptome analyses from ascites‐derived tumor cell spheroids ( n = 10) versus tumor samples from different metastatic sites ( n = 30) revealed upregulation of genes involved in chemoresistance ( TGM1 , HSPAs, MT1s), cell adhesion and cell‐barrier integrity ( PKP3 , CLDNs, PPL ), and the oxidative phosphorylation process. Mitochondrial markers (mass and membrane potential) showed a reduced mitochondrial function in tumoroids from tumor tissue compared with ascites‐derived tumor spheroids in flow cytometry analysis. Interestingly, response to OXPHOS inhibition by metformin and IACS010759 in tumor spheroids correlated with the extent of mitochondrial membrane potential measured by fluorescence‐activated cell sorting. Our data contribute to a better understanding of the biology of ovarian cancer spheroids and identify the OXPHOS pathway as new potential treatment option in advanced ovarian cancer.
