Browsing by Author "Kim, Jaeyeon"
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Item A Benzenesulfonamide-based Mitochondrial Uncoupler Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Epithelial Ovarian Cancer(American Association for Cancer Research, 2021) Bi, Fangfang; Jiang, Ziyan; Park, Wonmin; Hartwich, Tobias M. P.; Ge, Zhiping; Chong, Kay Y.; Yang, Kevin; Morrison, Madeline J.; Kim, Dongin; Kim, Jaeyeon; Zhang, Wen; Kril, Liliia M.; Watt, David S.; Liu, Chunming; Yang-Hartwich, Yang; Biochemistry and Molecular Biology, School of MedicineEpithelial ovarian cancer (EOC) is a leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOCs metastasize in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro-N-(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro. Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect ovarian cancer patients against relapse.Item Author Correction: CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity(Nature Publishing Group, 2018-04-13) Walton, Josephine B.; Farquharson, Malcolm; Mason, Susan; Port, Jennifer; Kruspig, Bjorn; Dowson, Suzanne; Stevenson, David; Murphy, Daniel; Matzuk, Martin; Kim, Jaeyeon; Coffelt, Seth; Blyth, Karen; McNeish, Iain A.; Biochemistry and Molecular Biology, School of MedicineA correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.Item Cell Origins of High-Grade Serous Ovarian Cancer(MDPI, 2018-11) Kim, Jaeyeon; Park, Eun Young; Kim, Olga; Schilder, Jeanne M.; Coffey, Donna M.; Cho, Chi-Heum; Bast, Robert C.; Biochemistry and Molecular Biology, School of MedicineHigh-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.Item CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity(Nature Publishing group, 2017-12-04) Walton, Josephine B.; Farquharson, Malcolm; Mason, Susan; Port, Jennifer; Kruspig, Bjorn; Dowson, Suzanne; Stevenson, David; Murphy, Daniel; Matzuk, Martin; Kim, Jaeyeon; Coffelt, Seth; Blyth, Karen; McNeish, Iain A.; Biochemistry and Molecular Biology, School of MedicineTransplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53 −/− clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten. We show that ID8 Trp53 −/−;Brca1 −/− and Trp53 −/−;Brca2 −/− cells have defective homologous recombination and increased sensitivity to both platinum and PARP inhibitor chemotherapy compared to Trp53 −/−. By contrast, loss of Pten or Nf1 increases growth rate in vivo, and reduces survival following cisplatin chemotherapy in vivo. Finally, we have also targeted Trp53 in cells isolated from a previous transgenic murine fallopian tube carcinoma model, and confirmed that loss of p53 expression in this second model accelerates intraperitoneal growth. Together, these CRISPR-generated models represent a new and simple tool to investigate the biology of HGSC, and the ID8 cell lines are freely available to researchers.Item Deep Metabolomics of a High-Grade Serous Ovarian Cancer Triple-Knockout Mouse Model(ACS, 2019) Huang, Danning; Gaul, David A.; Nan, Hongmei; Kim, Jaeyeon; Fernández, Facundo M.; Epidemiology, School of Public HealthHigh-grade serous carcinoma (HGSC) is the most common and deadliest ovarian cancer (OC) type, accounting for 70–80% of OC deaths. This high mortality is largely due to late diagnosis. Early detection is thus crucial to reduce mortality, yet the tumor pathogenesis of HGSC remains poorly understood, making early detection exceedingly difficult. Faithfully and reliably representing the clinical nature of human HGSC, a recently developed triple-knockout (TKO) mouse model offers a unique opportunity to examine the entire disease spectrum of HGSC. Metabolic alterations were investigated by applying ultra-performance liquid chromatography–mass spectrometry (UPLC–MS) to serum samples collected from these mice at premalignant, early, and advanced stages of HGSC. This comprehensive analysis revealed a panel of 29 serum metabolites that distinguished mice with HGSC from controls and mice with uterine tumors with over 95% accuracy. Meanwhile, our panel could further distinguish early-stage HGSC from controls with 100% accuracy and from advanced-stage HGSC with over 90% accuracy. Important identified metabolites included phospholipids, sphingomyelins, sterols, N-acyltaurine, oligopeptides, bilirubin, 2(3)-hydroxysebacic acids, uridine, N-acetylneuraminic acid, and pyrazine derivatives. Overall, our study provides insights into dysregulated metabolism associated with HGSC development and progression, and serves as a useful guide toward early detection.Item Effect of exercise on peritoneal microenvironment and progression of ovarian cancer(e-Century Publishing, 2021-10-15) Morrisson, Madeline J.; Bi, Fangfang; Yang, Kevin; Cady, Sarah L.; Hartwich, Tobias M.P.; Cerchia, Alexandra P.; Li, Zhigui; Kim, Jaeyeon; Irwin, Melinda L.; Yang-Hartwich, Yang; Biochemistry and Molecular Biology, School of MedicineOvarian cancer is one of the deadliest gynecological malignancies and lacks treatments that do not significantly impact patient health-related quality of life. Exercise has been associated with reduced cancer risk and improved clinical outcomes; however the underlying molecular mechanisms are unknown. In this study, we utilized a treadmill-running exercise model to investigate the effects of exercise on high-grade serous ovarian carcinoma (HGSOC) progression and chemotherapy outcomes. We found that treadmill-running suppressed peritoneal colonization of tumors in a syngeneic mouse ovarian cancer model. Acute exercise stimulated the production of CCL2 and IL-15 in the peritoneal microenvironment while downregulating CCL22, VEGF, and CCL12. Using a co-culture model, we demonstrated the role of CCL2 in mediating the activity of peritoneal cells to inhibit cancer cell viability. We showed that the activation of M1 macrophages may contribute to the exercise-induced changes in the peritoneal microenvironment. We identified that chronic exercise modulates gene expression of intraperitoneal fat tissues related to lipid formation, thermogenesis, browning, and inflammation, which can contribute to inhibiting the colonization of metastatic ovarian cancer. Treadmill running also lowered blood urea nitrogen levels and reduced incidence of neutropenia and thrombocytopenia during chemotherapy in a mouse model, suggesting the potential beneficial effects of exercise in improving chemotherapy outcomes. Our data provided new insights into the acute and chronic effects of physical activity on ovarian cancer at the molecular and in vivo levels.Item In vivo modeling of metastatic human high-grade serous ovarian cancer in mice(PLOS, 2020-06-04) Kim, Olga; Park, Eun Young; Klinkebiel, David L.; Pack, Svetlana D.; Shin, Yong-Hyun; Abdullaev, Zied; Emerson, Robert E.; Coffey, Donna M.; Kwon, Sun Young; Creighton, Chad J.; Kwon, Sanghoon; Chang, Edmund C.; Chiang, Theodore; Yatsenko, Alexander N.; Chien, Jeremy; Cheon, Dong-Joo; Yang-Hartwich, Yang; Nakshatri, Harikrishna; Nephew, Kenneth P.; Behringer, Richard R.; Fernández, Facundo M.; Cho, Chi-Heum; Vanderhyden, Barbara; Drapkin, Ronny; Bast, Robert C., Jr.; Miller, Kathy D.; Karpf, Adam R.; Kim, Jaeyeon; Biochemistry and Molecular Biology, School of MedicineMetastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.Item Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer(Cold Spring Harbor Laboratory, 2023-01-04) Bifarin, Olatomiwa O.; Sah, Samyukta; Gaul, David A.; Moore, Samuel G.; Chen, Ruihong; Palaniappan, Murugesan; Kim, Jaeyeon; Matzuk, Martin M.; Fernández, Facundo M.; Biochemistry and Molecular Biology, School of MedicineOvarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages, and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipids alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer.Item MiR-10a as a Modulator of Proliferation and Cell Cycle Progression in Ovarian Clear Cell Carcinoma(2024-08) Collins, Kaitlyn Elizabeth; Hawkins, Shannon; Kim, Jaeyeon; Mayo, Lindsey; Nephew, Kenneth; Zhang, Chi; Zimmers, TeresaEndometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a significant risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are a potential precursor lesion for ovarian clear cell carcinoma (OCCC). To explore the transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n=4) were compared to benign endometriomas (n=4) by bulk RNA and small-RNA sequencing. Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P<0.05, log2 fold-change>|1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of cell cycle regulation and DNA replication pathways and downregulation in cytokine receptor signaling and matrisome pathways. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P<0.05, log2 fold-change>|1|). Hsa-miR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2 fold change=4.37, P=2.43E-18; QPCR: 8.1-fold change, P<0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2=0.92). The cellular function of miR-10a was investigated by overexpressing miR-10a in vitro. MiR-10a overexpression revealed a significant decrease in proliferation (n=6; P< 0.05), compared to a non-targeting control. Cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 in (n=6; P<0.0001). MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival [SERPINE1 (3.2 downregulated; P<0.05), CDK6 (2.4 downregulated; P<0.05) and, RAP2A (2-3 downregulated; P<0.05)].Item Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis(MDPI, 2024-03-18) Haran, Shaun; Chindera, Kantaraja; Sabry, May; Wilkinson, Nafisa; Arora, Rupali; Zubiak, Agnieszka; Bartlett, Thomas E.; Evans, Iona; Jones, Allison; Reisel, Daniel; Herzog, Chiara; Alkasalias, Twana; Newman, Mark; Kim, Jaeyeon; Flöter Rådestad, Angelique; Gemzell-Danielsson, Kristina; Rosenthal, Adam N.; Dubeau, Louis; Lowdell, Mark W.; Widschwendter, Martin; Biochemistry and Molecular Biology, School of MedicineBackground: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. Methods: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. Results: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Conclusions: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.