Yong Sang Song

Modulation of Cisplatin Sensitivity through TRPML1-Mediated Lysosomal Exocytosis in Ovarian Cancer Cells: A Comprehensive Metabolomic Approach

Background: The lysosome has emerged as a promising target for overcoming chemoresistance, owing to its role in facilitating the lysosomal sequestration of drugs. The lysosomal calcium channel TRPML1 not only influences lysosomal biogenesis but also coordinates both endocytosis and exocytosis. This study explored the modulation of cisplatin sensitivity by regulating TRPML1-mediated lysosomal exocytosis and identified the metabolomic profile altered by TRPML1 inhibition. Methods: We used four types of ovarian cancer cells: two cancer cell lines (OVCAR8 and TOV21G) and two patient-derived ovarian cancer cells. Metabolomic analyses were conducted to identify altered metabolites by TRPML1 inhibition. Results: Lysosomal exocytosis in response to cisplatin was observed in resistant cancer cells, whereas the phenomenon was absent in sensitive cancer cells. Through the pharmacological intervention of TRPML1, lysosomal exocytosis was interrupted, leading to the sensitization of resistant cancer cells to cisplatin treatment. To assess the impact of lysosomal exocytosis on chemoresistance, we conducted an untargeted metabolomic analysis on cisplatin-resistant ovarian cancer cells with TRPML1 inhibition. Among the 1446 differentially identified metabolites, we focused on 84 significant metabolites. Metabolite set analysis revealed their involvement in diverse pathways. Conclusions: These findings collectively have the potential to enhance our understanding of the interplay between lysosomal exocytosis and chemoresistance, providing valuable insights for the development of innovative therapeutic strategies.

Mitochondrial fission enhances IL‐6‐induced metastatic potential in ovarian cancer via ERK1/2 activation

AbstractOvarian cancer is a lethal gynecologic cancer mostly diagnosed in an advanced stage with an accumulation of ascites. Interleukin‐6 (IL‐6), a pro‐inflammatory cytokine is highly elevated in malignant ascites and plays a pleiotropic role in cancer progression. Mitochondria are dynamic organelles that undergo fission and fusion in response to external stimuli and dysregulation in their dynamics has been implicated in cancer progression and metastasis. Here, we investigate the effect of IL‐6 on mitochondrial dynamics in ovarian cancer cells (OVCs) and its impact on metastatic potential. Treatment with IL‐6 on ovarian cancer cell lines (SKOV3 and PA‐1) led to an elevation in the metastatic potential of OVCs. Interestingly, a positive association was observed between dynamin‐related protein 1 (Drp1), a regulator of mitochondrial fission, and IL‐6R in metastatic ovarian cancer tissues. Additionally, IL‐6 treatment on OVCs was linked to the activation of Drp1, with a notable increase in the ratio of the inhibitory form p‐Drp1(S637) to the active form p‐Drp1(S616), indicating enhanced mitochondrial fission. Moreover, IL‐6 treatment triggered the activation of ERK1/2, and inhibiting ERK1/2 mitigated IL‐6‐induced mitochondrial fission. Suppressing mitochondrial fission through siRNA transfection and a pharmacological inhibitor reduced the IL‐6‐induced migration and invasion of OVCs. This was further supported by 3D invasion assays using patient‐derived spheroids. Altogether, our study suggests the role of mitochondrial fission in the metastatic potential of OVCs induced by IL‐6. The inhibition of mitochondrial fission could be a potential therapeutic approach to suppress the metastasis of ovarian cancer.

Impact of Changes in Obesity and Abdominal Obesity on Endometrial Cancer Risk in Young Korean Women: A Nationwide Cohort Study

Abstract Background: The increasing incidence of endometrial cancer in young women parallels the increasing prevalence of obesity, a well-established risk factor. However, the impact of longitudinal changes in obesity and abdominal obesity on early-onset endometrial cancer remains insufficiently understood. Methods: This nationwide cohort study utilized data from the Korean National Health Insurance Service. Women, ages 20 to 39 years, who underwent two health examinations at a 3-year interval between 2009 and 2015, with no history of cancer, were included. Participants were categorized based on changes in obesity (body mass index ≥25 kg/m2) or abdominal obesity (waist circumference ≥85 cm) into four groups: stable non-obese, non-obese to obese, obese to non-obese, and stable obese. The risk of endometrial cancer was assessed using Cox proportional hazards models. Results: Among 935,600 women, 798 developed endometrial cancer. Compared with the stable non-obese group, adjusted HRs for endometrial cancer were 1.940 (1.468–2.563), 2.083 (1.447–3.001), and 2.083 (1.447–3.001) in the non-obese to obese, obese to non-obese, and stable obese groups, respectively. With regard to abdominal obesity, the adjusted HRs were 2.048 (1.581–2.651), 2.302 (1.684–3.146), and 4.394 (3.557–5.427), respectively. The risk of cancer was higher in the obese to non-obese group than in the non-obese to obese group. Conclusions: Changes in obesity and abdominal obesity statuses were associated with early-onset endometrial cancer, with persistent abdominal obesity showing the highest risk. Impact: These findings support the need for early, sustained obesity interventions to reduce endometrial cancer risk in young women.

GNAi2/gip2-Regulated Transcriptome and Its Therapeutic Significance in Ovarian Cancer

Increased expression of GNAi2, which encodes the α-subunit of G-protein i2, has been correlated with the late-stage progression of ovarian cancer. GNAi2, also referred to as the proto-oncogene gip2, transduces signals from lysophosphatidic acid (LPA)-activated LPA-receptors to oncogenic cellular responses in ovarian cancer cells. To identify the oncogenic program activated by gip2, we carried out micro-array-based transcriptomic and bioinformatic analyses using the ovarian cancer cell-line SKOV3, in which the expression of GNAi2/gip2 was silenced by specific shRNA. A cut-off value of 5-fold change in gene expression (p < 0.05) indicated that a total of 264 genes were dependent upon gip2-expression with 136 genes coding for functional proteins. Functional annotation of the transcriptome indicated the hitherto unknown role of gip2 in stimulating the expression of oncogenic/growth-promoting genes such as KDR/VEGFR2, CCL20, and VIP. The array results were further validated in a panel of High-Grade Serous Ovarian Carcinoma (HGSOC) cell lines that included Kuramochi, OVCAR3, and OVCAR8 cells. Gene set enrichment analyses using DAVID, STRING, and Cytoscape applications indicated the potential role of the gip2-stimulated transcriptomic network involved in the upregulation of cell proliferation, adhesion, migration, cellular metabolism, and therapy resistance. The results unravel a multi-modular network in which the hub and bottleneck nodes are defined by ACKR3/CXCR7, IL6, VEGFA, CYCS, COX5B, UQCRC1, UQCRFS1, and FYN. The identification of these genes as the critical nodes in GNAi2/gip2 orchestrated onco-transcriptome establishes their role in ovarian cancer pathophysiology. In addition, these results also point to these nodes as potential targets for novel therapeutic strategies.

Computational modeling of malignant ascites reveals CCL5–SDC4 interaction in the immune microenvironment of ovarian cancer

AbstractFluid accumulation in the abdominal cavity is commonly found in advanced‐stage ovarian cancer patients, which creates a specialized tumor microenvironment for cancer progression. Using single‐cell RNA sequencing (scRNA‐seq) of ascites cells from five patients with ovarian cancer, we identified seven cell types, including heterogeneous macrophages and ovarian cancer cells. We resolved a distinct polarization state of macrophages by MacSpectrum analysis and observed subtype‐specific enrichment of pathways associated with their functions. The communication between immune and cancer cells was predicted through a putative ligand–receptor pair analysis using NicheNet. We found that CCL5, a chemotactic ligand, is enriched in immune cells (T cells and NK cells) and mediates ovarian cancer cell survival in the ascites, possibly through SDC4. Moreover, SDC4 expression correlated with poor overall survival in ovarian cancer patients. Our study highlights the potential role of T cells and NK cells in long‐term survival patients with ovarian cancer, indicating SDC4 as a potential prognostic marker in ovarian cancer patients.

Integrated analysis of ascites and plasma extracellular vesicles identifies a miRNA-based diagnostic signature in ovarian cancer

Ovarian cancer is mostly diagnosed at advantaged stages due to the lack of early diagnostic biomarkers. The common metastasis pattern is characterized by peritoneal dissemination with a formation of malignant ascites. Extracellular vesicles (EVs) are emerging as promising clinical biomarkers in liquid biopsy. Here, we aimed to investigate robust liquid biopsy-based EV miRNA biomarkers for ovarian cancer diagnosis and metastasis regulation. EVs were isolated from malignant ascites and plasma of ovarian cancer patients as well as the benign control counterparts of patients with benign gynecologic diseases. EV small RNA sequencing identified a panel of eight miRNAs (miR-1246, miR-1290, miR-483, miR-429, miR-34b-3p, miR-34c-5p, miR-145-5p, miR-449a) based on dysregulated miRNAs overlapped in the ascites and plasma subset. The ovarian cancer EV miRNA (OCEM) signature developed based on these eight miRNAs demonstrated high diagnostic accuracy in our in-house dataset and multiple public datasets across diverse clinical samples (blood, tissue and urine). In addition, malignant ascites-derived EVs could significantly facilitate the aggressive property of ovarian cancer cells and boost the growth of ascites-derived organoids. Notably, miR-1246 and miR-1290 shuttled in malignant ascites-derived EVs were identified to promote the invasion and migration of ovarian cancer cells through regulating a common target RORα.

Lymph Node Ratio Is a Strong Prognostic Factor in Patients with Early-Stage Cervical Cancer Undergoing Minimally Invasive Radical Hysterectomy

To determine whether the prognostic impact of lymph node ratio (LNR), defined as the ratio between the number of positive lymph nodes and removed lymph nodes, differs between open and minimally invasive surgical approaches for radical hysterectomy (RH) in node-positive, early-stage cervical cancer. We retrospectively identified 2009 International Federation of Gynecology and Obstetrics stage IB1-IIA2 patients who underwent primary type C RH between 2010 and 2018. Among them, only those with pathologically proven lymph node metastases who received adjuvant radiation therapy were included. The prognostic significance of LNR was investigated according to open surgery and minimally invasive surgery (MIS). In total, 55 patients were included. The median LNR (%) was 9.524 (range, 2.083-62.500). Based on receiver operating characteristic curve analysis, the cut-off value for LNR (%) was determined as 8.831. Overall, patients with high LNR (≥8.831%; n=29) showed worse disease-free survival (DFS) than those with low LNR (<8.831%, n=26) ( In patients with node-positive, early-stage cervical cancer, high LNR was associated with a significantly higher disease recurrence rate. This relationship was further consolidated among patients who received MIS RH.

Tailored chemotherapy: Innovative deep‐learning model customizing chemotherapy for high‐grade serous ovarian carcinoma