Ovarian Metastasis Research Articles

ROR2/Wnt5a signaling regulates early tumor cell invasion and metastasis in ovarian cancer

ROR2/Wnt5a signaling regulates early tumor cell invasion and metastasis in ovarian cancer

Molecular subtypes of endometrioid endometrial cancer predict rates of lymph node and ovarian metastasis at the time of surgical staging

Molecular subtypes of endometrioid endometrial cancer predict rates of lymph node and ovarian metastasis at the time of surgical staging

Impact of the tumor microenvironment in splenic metastasis in high-grade serous ovarian cancer revealed by quantitative proteomics

Impact of the tumor microenvironment in splenic metastasis in high-grade serous ovarian cancer revealed by quantitative proteomics

A novel ex vivo platform for personalized treatment of metastatic ovarian cancer

A novel ex vivo platform for personalized treatment of metastatic ovarian cancer

Long Non-coding RNA FOXD2-AS1 Silencing Inhibits Malignant Behaviors of Ovarian Cancer Cells Via miR-324-3p/SOX4 Signaling Axis.

It is urgent to develop new therapeutic strategies for ovarian cancer (OC). Long-noncoding RNAs (lncRNAs) have participated in multiple biological processes including tumor recurrence and progression. This study aimed to determine the effects and potential regulatory mechanism of lncRNA FOXD2-AS1 in OC progression. Levels of lncRNA FOXD2-AS1 and miR-324-3p in OC tissues and cell lines were analyzed using quantitative real-time PCR (qRT-PCR). The direct target between FOXD2-AS1 or miR-324-3p was determined using bioinformatics tools and further verified by dual-luciferase reporter assay. Cell viability, apoptosis, migration, along invasion were assessed by MTT, flow cytometry, as well as Transwell assays, respectively. In addition, the levels of miR-324-3p, PCNA, MMP9, Bax, Bcl-2, and SOX4 in OC cells were evaluated using qRT-PCR and western blot assays. We observed that lncRNA FOXD2-AS1 was up-regulated while miR-324-3p was down-regulated in OC tissues and cell lines, especially in SKOV3 cells. Moreover, miR-324-3p was a direct target of lncRNA FOXD2-AS1. Meanwhile, SOX4 interacted with miR-324-3p and was negatively regulated by miR-324-3p in SKOV3 cells. Function assays confirmed that lncRNA FOXD2-AS1 silenced depressed cell proliferation, migration, and invasion while accelerating apoptosis. These functions of lncRNA FOXD2-AS1 were attenuated by miR-324-3p inhibition. Our research demonstrated that FOXD2-AS1 silencing restrained cell growth and metastasis of OC via regulating miR-324-3p/SOX4 axis, indicating that lncRNA FOXD2-AS1 could be a novel potential therapeutic target for OC.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Chemoembolization, Radioembolization, and Percutaneous Ablation: New Opportunities for Treating Ovarian Cancer Liver Metastasis.

Parenchymal liver metastases from ovarian cancer, occurring in 2-12.5% of cases, significantly worsen prognosis. While surgery and systemic treatments remain primary options, unresectable or chemotherapy-resistant multiple liver metastases pose a significant challenge. Recent advances in liver-directed therapies, including radiofrequency ablation, microwave ablation, cryoablation, transarterial chemoembolization (TACE), and radioembolization, offer potential treatment alternatives. However, the efficacy of these techniques is limited by factors such as tumor size, number, and location. The ideal candidate for tumor ablation is a patient with paucifocal disease, a single tumor up to 5cm or up to 3 tumors smaller than 3cm and tumors 1cm away from major bile ducts and high-flow vessels. Transarterial chemoembolization could be performed in patients with less than 70% tumor load. Differently, radioembolization is available with less limitation on the sites or number of liver cancers. Radioembolization techniques are also able to downsize liver metastases. However, there are limited data regarding the outcomes of loco-regional therapy in patients with hepatic metastases from ovarian cancer. Advancing liver-directed therapies through interventional oncology, combined with robust data on the oncological efficacy of these local treatments, will validate their potential as effective locoregional therapies for liver metastases. This could offer a promising treatment option for patients with ovarian cancer and unresectable hepatic metastases.

Chemotherapy Sparks Tertiary Lymphoid Structures in Metastatic Ovarian Cancer.

Ovarian cancer remains resistant to immunotherapy in most patients, highlighting the need to make these tumors more immunogenic. A recent study unveils how chemotherapy is able to induce cancer cell stress in metastatic ovarian carcinomas, inducing the formation of tertiary lymphoid structures that create a "hotter" tumor microenvironment.

CypA/TAF15/STAT5A/miR-514a-3p feedback loop drives ovarian cancer metastasis.

Cyclophilin A (CypA) is a peptidyl-prolyl isomerase that participates in multiple cancer events, but the molecular mechanisms of abnormal expression and regulation of CypA in ovarian cancer (OC) have never been considered. This study identifies CypA as a key driver of epithelial-mesenchymal transition (EMT) in ovarian cancer and explores the mechanisms that underly this process. We show that CypA is upregulated in tissues and serum of ovarian cancer patients and that CypA overexpression correlates with poor prognosis. CypA facilitates tumor growth and metastasis in vivo in subcutaneous tumor xenograft and abdominal metastatic models, and in vitro studies suggest a mechanism, showing that CypA accelerates ovarian cancer cell epithelial-mesenchymal transition by activating a PI3K/AKT signaling pathway. Mechanistic studies showed that STAT5A binds pri-miR-514a-3p and inhibits its activity, whereas miR-514a-3p directly binds to the 3'-UTR of CypA to suppress its expression, resulting in STAT5A promoting the expression of CypA, forming the STAT5A/miR-514a-3p/CypA axis. Furthermore, immunoprecipitates and mass spectrometry analysis identifies a CypA interaction with TAF15 that stabilizes TAF15 by suppressing its proteasome degradation and promotes its entry into the nucleus. While STAT5A is positively regulated by TAF15. Our findings identify a novel feedback loop for CypA that drives EMT and ovarian tumor growth and metastasis via a TAF15/STAT5A/miR-514a-3p pathway in ovarian cancer and facilitates the release of CypA into the extracellular, which provides a promising therapeutic target for OC treatment and a diagnostic biomarker.

Unveiling the Uncommon: Ovarian Cancer Metastasis as a Rare Cause of Obstructive Jaundice and Partial Gastric Outlet Obstruction

Unveiling the Uncommon: Ovarian Cancer Metastasis as a Rare Cause of Obstructive Jaundice and Partial Gastric Outlet Obstruction

Berberine modulates ovarian cancer autophagy and glycolysis through the LINC01123/P65/MAPK10 signaling axis

BackgroundBerberine, a readily accessible natural compound known for its ease of synthesis and low toxicity, exhibits anti-tumor properties by modulating inflammatory responses. Recent studies have revealed that berberine can also treat malignant tumors by influencing tumor metabolic reprogramming, making it a potential candidate for metabolic therapy in ovarian cancer. MethodsThe anti-proliferative and anti-metastatic effects of berberine on ovarian cancer cells were investigated using CCK-8 assays, scratch assays, EDU proliferation assays, and assays related to glycolysis and autophagy. Differentially expressed lncRNAs in ovarian cancer were identified using data from the TCGA database. A specific lncRNA's role was delineated through RNA pulldown assays, silver staining, mass spectrometry analysis, CHIP assays, and immunoprecipitation experiments, focusing on its involvement in glycolysis and autophagy regulation in ovarian cancer. Additionally, the inhibitory mechanism of berberine on ovarian cancer cells was validated through cell thermal shift assays and cycloheximide protein degradation experiments to confirm its interaction with key targets. ResultsIn vitro experiments revealed that berberine reduces glycolysis and autophagy levels, leading to the inhibition of ovarian cancer cell proliferation and metastasis. Bioinformatics analysis of TCGA data identified LINC00123 as associated with poor prognosis in ovarian cancer. Experimental validation, including RNA pulldown assays, confirmed that the LINC00123/P65/MAPK10 signaling axis regulates glycolysis and autophagy in ovarian cancer. Furthermore, at the molecular level, berberine inhibits the interaction between LINC00123 and P65, thereby reducing P65 protein stability and impeding its transcriptional regulation of downstream MAPK10. These findings were further validated in animal models. ConclusionOur study highlights berberine's dual benefits of anti-inflammatory effects and inhibition of ovarian cancer proliferation and metastasis by modulating autophagy and glycolysis levels. Mechanistically, berberine targets the LINC00123/P65/MAPK10 signaling pathway to regulate glycolysis and autophagy in ovarian cancer. These insights not only expand the potential of berberine in ovarian cancer therapy but also provide new targets and therapeutic strategies for metabolic therapy in this cancer type.

7065 Eradication Of Metastatic ER-Positive Breast, Ovarian, Endometrial And Lung Cancer In Mouse Xenografts And Patient Derived Organoids

Abstract Disclosure: D.J. Shapiro: None. D. Duraki: None. S. Ghosh: None. J. Zhu: None. C. Mao: None. J. Kim: None. M. Jabeen: None. M.W. Boudreau: None. M.P. Mulligan: None. R. Romero: None. Y. Han: None. J. Zhang: None. E.R. Nelson: None. O. Olopade: None. G. Chang: None. P.J. Hergenrother: Advisory Board Member; Self; Systems Oncology. We described the tumor protective estrogen-ER activated anticipatory Unfolded Protein Response (a-UPR) pathway. Here we report a previously undescribed multistep pathway by which very rapid estrogen-ER activation of the a-UPR authorizes and regulates subsequent transcription of the estrogen-ER transcriptome. We repurposed the tumor protective a-UPR through identification and optimization of the small molecule ErSO and its family of agents. ErSO acts non-competitively with estrogen to induce lethal hyperactivation of the a-UPR. In orthotopic mouse xenografts containing wild type or mutant ER, ErSO often induced complete regression without recurrence of large primary breast tumors and of most lung, bone and liver metastases, near complete regression of normally lethal brain metastases and complete destruction of patient derived organoids (PDOs) in Matrigel. Six research teams in four locations have confirmed the remarkable effectiveness of ErSO in ER-positive breast cancer. We next evaluated ErSO in diverse ER containing cancers in which estrogen is not the primary driver of proliferation. ErSO often induced complete regression in multiple orthotopic xenograft models of primary and metastatic ovarian cancer. Using fresh ovarian cancer organoids immediately after removal from patients by paracentesis, ErSO destroyed the organoids from some patients with advanced stage III and stage IV disease. ErSO was effective in a mouse xenograft model of endometrial cancer and, surprisingly, even in ERalpha positive lung cancer. Our ongoing studies demonstrate ErSO induces complete, or near complete regression, of primary and metastatic lung cancer in mice. Studies of ErSO’s mechanism of action using genome-wide CRISPR screens with positive selection, and other techniques, unveil a novel death pathway in which ErSO activation of the a-UPR triggers rapid calcium release into the cell body. The calcium opens the plasma membrane TRPM4 sodium channel, leading to an influx of extracellular sodium. This swells the cells, resulting in osmotic stress that sustains lethal a-UPR activation. A little-studied cytoskeleton regulator we identified, FGD3, plays a pivotal role in whether the cells rupture their membranes, inducing necrotic cell death. Notably, medium from diverse cancer cells killed by ErSO-induced necrosis robustly activates human macrophage and induces their migration - potentially facilitating immunotherapy. These studies describe a pathway from a multiprotein ER-SRC-PLC complex, through the a-UPR, to a novel cell swelling and necrosis pathway, that we are exploiting to target diverse, therapeutically challenging, ER-positive human cancers. Presentation: 6/2/2024

Ironing Out the Kinks: Arming Natural Killer Cells against Ovarian Cancer.

Ameliorating the tumor immune microenvironment is a key strategy to improve the therapeutic outcomes of patients with cancer. Sandoval and colleagues demonstrate that iron chelation enhances type I IFN production, promotes NK cell tumor trafficking and activation, and synergizes with chemotherapy drug cisplatin to reduce metastatic ovarian cancer progression in murine models. See related article by Sandoval et al., p. 1901.

Epithelial splicing regulatory protein 1 promotes peritoneal dissemination of ovarian cancer by inducing the formation of circular RNAs modulating epithelial plasticity.

Peritoneal metastases prevalently occur in ovarian cancer, deteriorating patient prognosis. During the metastatic cascade, tumor plasticity enables cells to adapt to environmental changes, thereby facilitating dissemination. We previously found that epithelial splicing regulatory protein 1 (ESRP1) is linked to peritoneal metastasis and epithelial-mesenchymal plasticity in ovarian cancer. This study delves into the underlying mechanism. We found that ESRP1 preserves epithelial plasticity in ovarian cancer cells in vitro and in vivo. Functionally, ESRP1 enhances ovarian cancer cell growth and peritoneal dissemination. High-throughput sequencing revealed several ESRP1-related epithelial RNAs, encompassing both linear and circular forms. Specifically, ESRP1 triggers the cyclization of circPAFAH1B2 and circUBAP2 through binding to the GGU sequences in adjacent introns. The two ESRP1-induced circular RNAs stabilize DKK3 and AHR mRNAs, which are critical for epithelial plasticity, through interaction with IGF2BP2. Collectively, ESRP1 triggers the formation of circPAFAH1B2 and circUBAP2, which in turn stabilizes DKK3 and AHR through IGF2BP2 binding, thereby modulating the epithelial plasticity and aiding the peritoneal spread of ovarian cancer cells. The findings unveiled a biological network, orchestrated by ESRP1, that governs the epithelial-mesenchymal plasticity of ovarian cancer cells, emphasizing the therapeutic potential of ESRP1 and its induced circular RNAs for ovarian cancer treatment.

7065 Eradication of Metastatic ER-positive Breast, Ovarian, Endometrial and Lung Cancer in Mouse Xenografts and Patient Derived Organoids

7065 Eradication of Metastatic ER-positive Breast, Ovarian, Endometrial and Lung Cancer in Mouse Xenografts and Patient Derived Organoids

Metallic-based phthalocyanine nanoemulsions for photodynamic purging of ovarian tissue in leukemia patients

For cancer patients with a high risk of ovarian tissue metastasis, ovarian autotransplantation is not advised due to the potential spread of malignant cells. Ex vivo purging of ovarian fragments may offer a more suitable alternative for fertility restoration. Eradicating malignant cells should be done selectively without affecting follicles or ovarian stromal cells (SCs). As a clinically licensed method, photodynamic therapy (PDT) is a minimally invasive treatment to destroy cancer cells. This study evaluates the effectiveness of nanoemulsions (NE) containing two phthalocyanine photosensitizers; aluminum (III) phthalocyanine (AlPc) and zinc (II) phthalocyanine (ZnPc) in eliminating cancer cells. Human leukemic malignant (HL-60) and ovarian stromal cells (SCs) were treated with AlPc/ZnPc loaded NEs with or without diode laser irradiation. HL-60 leukemia cells in 2D culture were eliminated by treatment with 10nM AlPc-NE or 0.1µM ZnPc-NE, while no toxicity was observed in SCs. In 3D culture models, although the cells showed more resistance to the NEs as a result of limited oxygen and photosensitizer penetration, the treatment remained selective for cancer cells. These approaches have the potential to eliminate malignant cells from ovarian tissue fragments.

Implementation of enhanced recovery protocols in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for metastatic ovarian cancer following neoadjuvant chemotherapy. A feasibility study

ObjectiveThe aim of this study is to evaluate the implementation of the elements of enhanced recovery (ERAS) protocols in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for metastatic ovarian cancer. ERAS protocols have shown improvement in the perioperative outcomes of patients who underwent cytoreductive surgery for metastatic ovarian cancer by reducing the length of stay as well as the postoperative complications and by improving patients’ postoperative experience. MethodsThis is a feasibility study involving retrospective analysis from (31) patients who underwent cytoreductive surgery and HIPEC versus (35) a control group that underwent cytoreductive surgery only, prior to the introduction of the HIPEC programme for metastatic ovarian cancer. All patients had undergone neoadjuvant chemotherapy prior to surgery. We compared the compliance for each element of the ERAS protocol between the two study groups. ResultsWe analyzed data from 66 patients, 31 in HIPEC group and 35 in the control goup. We found no significant difference in the patients’ characteristics between the two groups and there were no differences in the implementation of 8 elements of the ERAS protocols (100 % for both groups). The use of nasogastric tube was more frequently observed in patients undergoing surgery and HIPEC compared to those undergoing surgery alone (42 % vs 0 %, respectively; p < 0.001). The number of patients who were mobilized on the first postoperative day was higher in the group undergoing surgery and HIPEC (87.1 % vs 57.1 %, respectively; p = 0.007), however there was no significant difference in the percentage of patients that had early removal of the urinary catheter (p = 0.12), nor in the percentage of patients that received early feeding (p = 0.18). Finally, there were no statistically significant differences in the complication rates, the length of hospital stay and the re-admission rates between the two groups. ConclusionEnhanced recovery protocols can be implemented safely in patients undergoing cytoreductive surgery and HIPEC for ovarian cancer.

The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer

Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1+ GC cells. Collectively, our findings reveal that ER+ ovarian fibroblasts secrete MDK under estrogen influence, driving OM of GC via the MDK-LRP1 axis. Our study holds the potential to catalyze innovative therapeutic strategies aimed at intercepting and managing OM in GC.

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer.

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval: 2.5-15.9%). Three patients with MSS CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2 amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

The chromatin landscape of high-grade serous ovarian cancer metastasis identifies regulatory drivers in post-chemotherapy residual tumour cells

Disease recurrence following chemotherapy is a major clinical challenge in ovarian cancer (OC), but little is known regarding how the tumour epigenome regulates transcriptional programs underpinning chemoresistance. We determine the single cell chromatin accessibility landscape of omental OC metastasis from treatment-naïve and neoadjuvant chemotherapy-treated patients and define the chromatin accessibility profiles of epithelial, fibroblast, myeloid and lymphoid cells. Epithelial tumour cells display open chromatin regions enriched with motifs for the oncogenic transcription factors MEIS and PBX. Post chemotherapy microenvironments show profound tumour heterogeneity and selection for cells with accessible chromatin enriched for TP53, TP63, TWIST1 and resistance-pathway-activating transcription factor binding motifs. An OC chemoresistant tumour subpopulation known to be present prior to treatment, and characterised by stress-associated gene expression, is enriched post chemotherapy. Nuclear receptors RORa, NR2F6 and HNF4G are uncovered as candidate transcriptional drivers of these cells whilst closure of binding sites for E2F2 and E2F4 indicate post-treated tumour having low proliferative capacity. Delineation of the gene regulatory landscape of ovarian cancer cells surviving chemotherapy treatment therefore reveals potential core transcriptional regulators of chemoresistance, suggesting novel therapeutic targets for improving clinical outcome.