Causal effects of telomere length on ovarian tumor risk: Insights from genetic evidence.

Integration of coagulation parameters Enhances deep Learning-Based survival prediction in High-Grade serous ovarian Cancer: A comprehensive prognostic model.

Multitarget drugs represent one of the most appropriate responses to a multifaceted and elusive disease such as cancer. Besides, the option of introducing more active substances in a single compound may prove beneficial to simplify the administration of the drug and improve its pharmacokinetics. Here, the synthesis of a new class of palladium(0) complexes coordinating one molecule of Juglone has been developed, optimizing a versatile method that allows to easily select the kind of ancillary ligands, including phosphines, arsines, isocyanides, and N-heterocyclic carbenes. All the newly synthesised metal compounds have been fully characterized by spectroscopic methods and, in some cases, by X-ray diffractometry. Juglone is a natural-source organic compound derived from many species of the Juglandaceae family, whose therapeutic properties have long been known. In particular, its inhibitory activity toward PIN1-a fast-acting enzyme upregulated in cells and tissues of various neoplasms, especially ovarian cancer-can be exploited to reduce tumor proliferation. On the other hand, some of our previous works have shown the antiproliferative activity of different palladium(0) derivatives, in particular towards ovarian cancer cells. In this work, we prove that the η2-coordination of Juglone on the palladium(0) center can, in some cases, amplify its in vitro anticancer activity towards different ovarian cancer cell lines, probably by leveraging the combined effect of the natural organic molecule and the metal residue. A further added value is represented by the reduced cytotoxicity exhibited by most of our palladium complexes against MRC-5 non-cancerous cells (IC50 > 100 μM). At the same time, our synthesized complexes maintain high effectiveness against cisplatin-resistant and high-grade serous ovarian cancer cell lines, with IC50 values in the micromolar range. Finally, western blot analysis carried out on one of the most active complexes has proven its high inhibitory effect on the PIN1 oncogenic protein.

ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer.

RECQL4 as a novel drug target against ovarian cancer.

Aberrant glycosylation is recognized as a trait of tumorigenesis. Paucimannosidic glycoepitopes (PME), a class of small mannosidic N-linked glycans have recently been linked to pathophysiologic conditions such as cancer and infection. This study aimed to investigate whether paucimannosylation is present in ovarian cancer and to explore its prognostic relevance. We investigated the presence of PMEs in 176 patients with high-grade serous ovarian cancer using the research Mannitou antibody for immunohistochemistry. Immunohistochemical staining was assessed using eight different scoring systems and correlated with survival using the Kaplan-Meier method. Positive immunohistochemical staining of PMEs in immune cells was associated with improved 5-year disease-free survival (16.06% vs. 6.16%; p=0.032) and a trend toward improved 5-year overall survival (42.20% vs. 36.70%; p=0.052). Focal hot spot PME staining affecting more than 50% of tumor cells was associated with reduced 5-year overall survival (46.23% vs. 23.68%; p=0.029). Clinical factors such as tumor load, tumor distribution or FIGO-Stage showed no association with any PME staining pattern. Paucimannosylation, indicated by the presence of PMEs, is present in both tumor and immune cells in high-grade serous ovarian cancer. The prognostic implication of PMEs seems to be cell type-dependent. While immune cell paucimannosylation was associated with improved survival, tumor cell paucimannosylation was associated with reduced survival.

Objectives: BRCA1-mutated ovarian cancer is characterized by impaired DNA double-strand break repair and homologous recombination deficiency, leading to distinct tumor biology and therapeutic responses. Competing endogenous RNA networks have emerged as important regulatory mechanisms in cancer progression. This study aimed to investigate the functional and clinical significance of the HOTAIR–miR34a–CCND1 axis in BRCA1-mutated ovarian cancer. Methods: Transcriptomic and clinical data of high-grade serous ovarian cancer patients were obtained from the TCGA-OV cohort via the GDC portal. Differential gene expression analysis was performed using edgeR, while pathway enrichment analysis was conducted with clusterProfiler and KEGG. Survival analyses were evaluated using Kaplan–Meier curves. Results: The HOTAIR–miR34a–CCND1 axis displayed distinct expression profiles in BRCA1-mutated ovarian cancer tissues compared to wild-type cases. Kaplan–Meier survival analysis revealed no statistically significant differences in overall survival based on the expression levels of these genes (p > 0.05). However, KEGG pathway enrichment analysis demonstrated that these genes are involved in cancer-associated microRNA pathways, suggesting their potential role in tumor progression despite the lack of direct survival association. Conclusion: The HOTAIR–miR-34a–CCND1 axis may represent a potential prognostic biomarker and therapeutic target in BRCA1-mutated ovarian cancer, supporting the development of novel strategies such as HOTAIR inhibition, miR-34a replacement, or combination with PARP and CDK4/6 inhibitors.

High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor-infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management. Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis. The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors. CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.

BackgroundHigh-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy marked by widespread metastasis, most notably to the omentum. However, the molecular mechanisms driving this process remain poorly understood.MethodsWe present an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from normal ovaries, primary tumors, and omental metastases to generate a high-resolution cellular landscape of HGSOC. LAPTM5 expression was examined by immunohistochemistry, immunofluorescence, qPCR, western blotting, and analyses of TCGA datasets. Functional assays including Transwell migration/invasion, wound healing, flow cytometry, single-nucleotide variant (SNV) and alternative splicing (AS) analysis were performed after LAPTM5 knockdown. The proteins expression involved in epithelial-mesenchymal transition (EMT) and TGF-β mediated signaling pathways was verified by qPCR and western blotting. The critical role of LAPTM5 on metastasis in vivo was detected by the tumor-bearing mice model.ResultsWe identified a metastasis-associated epithelial subcluster characterized by immune suppression and poor prognosis, with LAPTM5 emerging as a defining marker. Functional assays revealed that LAPTM5 silencing significantly impaired HGSOC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and reduced metastatic burden in vivo. Mechanistically, LAPTM5 activates the TGF-β/Smad signaling pathway, promoting EMT and facilitating omental metastasis. Intriguingly, LAPTM5 knockdown led to reduced single-nucleotide variant (SNV) accumulation and alternative splicing (AS) events, thereby decreasing the expression of metastasis-associated genes.ConclusionsThese findings identify LAPTM5 as a key regulator of TGF-β/Smad-driven epithelial plasticity and omental dissemination in HGSOC, positioning it as both a prognostic biomarker and a potential therapeutic target for advanced-stage disease.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07319-z.

High-grade serous ovarian cancer (HGSC) accounts for more than 70% of ovarian cancer-related deaths, yet therapeutic progress remains stagnant. Among the four molecular subtypes reported for HGSC, the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio. However, the molecular drivers of this immune desert state remain largely undefined. Here, we identify RNA-binding proteins (RBPs) as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing. We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo. Mechanistically, IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation, thereby suppressing MHC-I presentation. We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo. Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype. This subtype-wide survey uncovers a previously unrecognized RBP-interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.

The accumulation of malignant ascites in the peritoneal cavity is a hallmark of high-grade serous ovarian cancer (HGSC). This fluid contains three-dimensional multicellular aggregates known as spheroids, which contribute to chemoresistance and are an accessible source of tumor material for proteomic-based biomarker discovery studies. Although heterogeneous ascitic spheroids can be generated from primary cell suspensions for ex vivo applications, they suffer from long generation times and reduced biological relevance. Here, we compare their ex vivo chemotherapy responses and proteomes to native spheroids that are collected directly from HGSC ascites, with the aim of assessing their suitability for proteomic-based chemoresponse prediction strategies that yield results within a clinically relevant time frame. We demonstrate that the chemoresponses of native spheroids better correlate with patients' clinical treatment responses in 4 of 5 cases and that their proteomes uniquely segregate according to ex vivo carboplatin response along the first component. This pilot study suggests key proteins and biological pathways that may facilitate a global proteomic-based screening strategy for personalized HGSC treatment, with particular emphasis on extracellular matrix proteins. As such, native spheroids have the potential to progress the personalized treatment of HGSC patients with malignant ascites.

Background. Platinum-based chemotherapy may be active in relapsed ovarian cancer (OC) regardless of the platinum-free interval (PFI). Aim. To clarify the role of platinum agents in the treatment of platinum-resistant recurrences of OC. Materials and methods. Patients with recurrent serous or endometrioid high-grade OC with PFI of ≤ 6 months treated between 2014 and 2024 were included in the study. Patients could receive standard non-platinum-based or platinum-based chemotherapy for the first or second recurrence of OC, with or without bevacizumab. Patients were excluded if they were platinum-refractory, had previously received more than 2 lines of systemic chemotherapy or had maintenance therapy with poly(ADP-ribose) polymerases inhibitors. The primary endpoint of the study was progression-free survival (PFS). The statistical hypothesis assumed the inclusion of ≥ 350 patients to identify clinically relevant differences (reduction in hazard ratio (HR) of ≥ 30 %) in PFS between study arms, with an expected median PFS in the control group equal to 4 months (with p = 0.05 and p = 0.2). Results. A total of 354 patients were included, significant imbalances were noted between arms in the frequency of pathogenic BRCA1/2 mutations (p = 0.039), duration of PFI (p 0.001), and administered non-platinum agents. Median PFS was 7.4 months and 3.2 months in platinum-based and non-platinum-based chemotherapy arms, respectively (HR 0.44; p 0.001), and median overall survival was 23.0 months and 16.5 months (HR 0.73; p = 0.011). Multivariate analysis confirmed independent effect of platinum-based chemotherapy on PFS (HR 0.57; p 0.001). Conclusion. The results of this study suggest superior efficacy of platinum-based chemotherapy in the treatment of early recurrences of OC. Prospective studies are needed to confirm these findings.

Prognostic significance of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting response to neoadjuvant chemotherapy in advanced high-grade serous ovarian cancer: a prospective study.

Resistance to apoptosis-inducing chemotherapy is a major factor contributing to treatment failure and poor survival outcomes in high-grade serous ovarian cancer (HGSOC). Ferroptosis, a regulated form of cell death driven by lipid peroxidation, has emerged as a promising effector mechanism because it remains available in HGSOC cells with impaired apoptosis signaling. While most research has focused on pharmacological ferroptosis inducers, there is growing interest in strategies that could trigger lipid autoxidation through externally delivered energy, such as photons. Photodynamic therapy (PDT), which utilizes light and light-activatable photosensitizers to generate reactive molecular species, offers a means of initiating lipid peroxidation with a high degree of precision and minimal systemic toxicities. However, the precise lipid targets of PDT, the influence of varying tumor lipidomic landscapes, and the role of ferroptosis sensitivity on PDT-lipid interactions have yet to be elucidated. In this study, we systematically compare PDT to ferroptosis induced by the inhibition of glutathione peroxidase 4, focusing on lipid redox states and composition in HGSOC cell lines. While PDT was similarly effective in both ferroptosis-sensitive and -resistant cells, its effects on cellular lipidomes differed markedly. PDT robustly induced lipid radical formation in both cell types; however, a dose-dependent accumulation of lipid hydroxides and hydroperoxides was only observed in ferroptosis-sensitive cells rich in unsaturated phospholipids. Further analysis revealed a significant overlap in lipid oxidation targets between PDT and ferroptosis. Notably, in both cell types, and in vivo, PDT upregulated ceramides, a lipid class strongly associated with mitochondrial apoptosis. In summary, PDT exhibited comparable efficacy in both ferroptosis-sensitive and -resistant cells by triggering a combination of lipid peroxidation and ceramide upregulation, suggesting the activation of both ferroptosis and apoptosis pathways. Further studies are needed to explore the role of PDT-induced lipidomic changes in the initiation of various cell death pathways and in overcoming chemoresistance in HGSOC.

High-grade serous ovarian cancer (HGSOC) is the most commonly diagnosed ovarian cancer subtype. Approximately half of all patients diagnosed with HGSOC are deficient in homologous recombination (HR), harbor BRCA1/2 mutations, and are treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). FDA-approved PARPis Olaparib, Niraparib, and Rucaparib all contribute to adverse effects in patients due to their poly-pharmacological properties. This feature necessitates investigation of global protein responses to PARPi treatment beyond DNA repair in the context of BRCA mutational status and HR deficiency. We sought to determine the landscape of differential PARPi-induced proteomes in HGSOC cells exhibiting different BRCA1/2 mutational statuses. Here, we applied immunofluorescence microscopy to detect γH2AX, Rad51, and geminin foci as markers of DNA damage and repair upon treatment of HGSOC cells with IC50 doses of PARPis. Global proteome perturbations upon PARPi treatment were measured using quantitative mass spectrometry-based proteomics. The proteomic data highlighted cell line effects, masking high-dose PARPi treatment response. Interrogation of PARPi response within biological pathways identified through gene set enrichment analysis (GSEA) revealed significant changes to proteins involved in Epithelial–Mesenchymal Transition (EMT), E2F targets, and cholesterol homeostasis. Our study establishes proteomic evidence supporting the poly-pharmacological characteristics of Niraparib, Olaparib, and Rucaparib in HGSOC cells.

High-grade serous ovarian cancer (HGSOC) is a poor prognostic disease, especially in BRCA1/2 wild-type (BRCA-WT) patients with homologous recombination (HR) proficiency. These patients often show limited response to both platinum-based chemotherapy and PARP inhibitors. HR and non-homologous end joining (NHEJ) are the two major DNA double-strand break (DSB) repair pathways. HR is a precise repair mechanism for DSBs but is limited to S and G2 phases. In contrast, NHEJ functions more broadly throughout the cell cycle, including G1. We investigated whether inhibiting the G2/M checkpoint kinases PLK1 or WEE1 individually could disrupt mitotic control and expose therapeutic vulnerabilities in BRCA-WT/HR-proficient HGSOC cells. We evaluated cell cycle–targeted strategies to overcome HR-proficient chemoresistance using either volasertib (a selective PLK1 inhibitor) or adavosertib (a potent WEE1 inhibitor) in BRCA-WT/HR-proficient and BRCA-mutant/HR-deficient HGSOC models. Both agents induced DNA damage, impaired HR repair (reduced RAD51 foci), and triggered mitotic catastrophe—a form of cell death caused by defective mitosis and unresolved DNA damage—in BRCA-WT cells. Volasertib caused polyploidy and abnormal spindle formation, indicating mitotic slippage and cytokinesis failure, whereas adavosertib abrogated the G2/M checkpoint, forcing premature mitotic entry. In contrast, BRCA-mutant cells were resistant to either volasertib or adavosertib, consistent with sustained and functional NHEJ activity. This resistance was restored by the pharmacological or genetic inhibition of DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), a prominent component of NHEJ. Functional and xenograft models confirmed selective vulnerability of BRCA-WT tumors to either PLK1 or WEE1 inhibition. Our work highlights a mechanistic framework linking cell cycle checkpoint inhibition to DNA repair pathway selectivity, providing a rationale for targeting mitotic regulators in HR-proficient ovarian cancer—a subgroup with high clinical unmet need.

Evaluating patient perspectives about the acceptability of a novel prognostic gene expression signature for high grade serous ovarian cancer: The OTTA-SPOT study.

Co-targeting the PI3K-Akt pathway improves response to MEK inhibition in low-grade serous ovarian cancer cell lines.

Quantifying opportunities to reduce high grade serous ovarian cancer via opportunistic salpingectomy.

Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma.