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  • 1
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    Online Resource
    Abstract 1682: Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1682-1682
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1682-1682
    Abstract: Objective: Patient-derived samples present an advantage over current cell line models of high grade serous ovarian cancer (HGSOC), which are flawed in terms of being reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we characterized a panel of patient-derived cells to determine their epithelial and mesenchymal characteristics, invasiveness, proliferation, stemness, and in vivo growth. Experimental procedures: Patient-derived xenograft (PDX) models of HGSOC were analyzed in vitro for phenotypic (RNA, let-7 miRNA, and protein expression, flow cytometry) and functional aspects including growth in spheroids, wound healing assays, invasion assays and in vivo (orthotopic PDX) growth characteristics. Results: Samples fell along the spectrum from epithelial to mesenchymal, and all had hybrid characteristics. Those toward the more epithelial end of the spectrum were most active in self-renewal assays, and grew most robustly in orthotopic xenograft models. Chemoresistance correlated both with the mesenchymal state and with BRCA2 wild type status. Loss of microRNA let-7 (lethal-7) is an important component of the cancer stem cell phenotype, and we observed an inverse association between let-7 expression and the epithelial state. We observed lower levels of let-7, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy in cells with the most epithelial phenotype. Conclusions: Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: epithelial cells (those with least let-7 expression) were less migratory, but more tumorigenic, than the mesenchymal cells with higher let-7 expression. We conclude that epithelial/mesenchymal state and let-7 expression are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo. Citation Format: Juli Unternaehrer, Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee Martine, Christine Castañón, Saied Mirshahidi, Marcelo Vazquez, Kerby C. Oberg, Yevgeniya J. Ioffe. Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1682.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1682
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 18 ( 2021-09-15), p. 4617-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 18 ( 2021-09-15), p. 4617-
    Abstract: High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13184617
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 3
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    Online Resource
    Epithelial/mesenchymal heterogeneity of high‐grade serous ovarian carcinoma samples correlates with miRNA let‐7 levels and predicts tumor growth and metastasis
    Wiley ; 2020
    In:  Molecular Oncology Vol. 14, No. 11 ( 2020-11), p. 2796-2813
    Details
    In: Molecular Oncology, Wiley, Vol. 14, No. 11 ( 2020-11), p. 2796-2813
    Abstract: Patient‐derived samples present an advantage over current cell line models of high‐grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient‐derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient‐derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial‐to‐mesenchymal state. Samples with a stronger epithelial phenotype were more active in self‐renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let‐7 ( lethal‐7 ) expression and stemness, consistent with the loss of let‐7 being an important component of the cancer stem cell phenotype. We observed that lower let‐7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum‐based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let‐7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let‐7 levels. We conclude that let‐7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self‐renewal, and tumor burden in vivo .
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.v14.11
    DOI: 10.1002/1878-0261.12762
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 4
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    Online Resource
    Abstract TMIM-065: MICRO-RNA LET-7 REGULATION AND FUNCTION IN OVARIAN CANCER AND EARLY EMBRYONIC DEVELOPMENT
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 22_Supplement ( 2019-11-15), p. TMIM-065-TMIM-065
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 22_Supplement ( 2019-11-15), p. TMIM-065-TMIM-065
    Abstract: INTRODUCTION: Epithelial ovarian cancer (EOC) is the fifth deadliest malignancy in women in the United States, with a high death-to-incidence ratio and five-year survival of 30%. Aggressiveness and recurrence of EOC has been attributed to cancer stem cells (CSC) within tumors, which contribute to chemoresistance and relapse. Deregulation of miRNAs has been linked to cancer initiation, progression, and the stem cell state. We focus on let-7 miRNA, which is repressed in many cancers and is associated with decreased survival. Let-7 is essential for cell differentiation, and its repression is required for reprogramming. Decreased let-7 level in cancer is associated with stemness. OBJECTIVE: Purpose for our research is to understand let-7 expression and function in EOC cell-lines and patients-derived samples in order to understand mechanisms of its abnormal regulation and develop novel treatments. MATERIALS AND METHODS: Patient-derived samples are used along with EOC cell-lines. Over-expression of Let-7 is achieved by mimic transfection and confirmed via RT-qPCR. Level of miRNA and pluripotency markers mRNA is detected via RT-qPCR, and protein expression confirmed by Western blot. Functional assays to analyze cancer phenotype include wound healing, invasion and spheroid formation assays. Embryoid body (EB) formation is used to mimic murine early embryonic development and guided toward primitive streak via cytokines. Let-7 expression is analyzed via RT-qPCR. RESULTS: We demonstrate that patient-derived EOC samples have decreased Let-7 levels and increased expression of pluripotency markers, therefore, we hypothesize that up-regulation of let-7 in EOC will decrease aggressiveness and increase chemosensitivity. We have demonstrated that up-regulation of let-7 via mimic transfection reduced cancer stem cell properties demonstrated by reduction of pluripotency markers and spheroid formation. Let-7 also decreased in vitro migration and invasion. Our data show that let-7 suppresses stem cell-like phenotype of EOC, indicating that it may be a treatment option in conjunction with conventional chemotherapies. In order to understand deregulation of let-7 in cancer, understanding its normal regulation and function during development is essential. By using mESCs we demonstrate that let-7 is dynamically expressed, contradicting conventional belief that let-7 levels slowly increase upon differentiation. Previously published data demonstrating that Hmga2, a let-7 target, peaks and is required upon exit from pluripotency supports our results. CONCLUSION: In conclusion, let-7 is repressed in EOC, and its over-expression demonstrates tumor suppressive functions via decreasing stemness, migration, invasion, and spheroid formation. During development let-7 is dynamically expressed, demonstrating complex regulation. Citation Format: Evgeny A Chirshev, Anthony Nguyen, Hojo Nozomi, Hill Alyse, Juli Unternaehrer. MICRO-RNA LET-7 REGULATION AND FUNCTION IN OVARIAN CANCER AND EARLY EMBRYONIC DEVELOPMENT [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-065.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.OVCASYMP18-TMIM-065
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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