Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk
Summary: The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling b...
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doaj-0997e8ecfa2743a797aa257846e3877d2020-11-25T01:43:43ZengElsevierCell Reports2211-12472019-12-01291240864098.e6Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal CrosstalkPeter C. Hart0Hilary A. Kenny1Niklas Grassl2Karen M. Watters3Lacey M. Litchfield4Fabian Coscia5Ivana Blaženović6Lisa Ploetzky7Oliver Fiehn8Matthias Mann9Ernst Lengyel10Iris L. Romero11Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USADepartment of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USADepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, GermanyDepartment of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USADepartment of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USADepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, GermanyWest Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USAWest Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USAWest Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USADepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, GermanyDepartment of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA; Corresponding authorDepartment of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA; Corresponding authorSummary: The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin. : Hart et al. identify that the type 2 diabetes drug metformin inhibits ovarian cancer invasion by targeting crosstalk between cancer cells and adjacent normal stromal mesothelial cells, making the microenvironment less hospitable to cancer growth. Keywords: mesothelial cells, tumor microenvironment, ovarian cancer, metformin, HIF1, SUCLG2, IL-8, TGF, omental metastasis, succinatehttp://www.sciencedirect.com/science/article/pii/S2211124719315700 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Peter C. Hart Hilary A. Kenny Niklas Grassl Karen M. Watters Lacey M. Litchfield Fabian Coscia Ivana Blaženović Lisa Ploetzky Oliver Fiehn Matthias Mann Ernst Lengyel Iris L. Romero |
spellingShingle |
Peter C. Hart Hilary A. Kenny Niklas Grassl Karen M. Watters Lacey M. Litchfield Fabian Coscia Ivana Blaženović Lisa Ploetzky Oliver Fiehn Matthias Mann Ernst Lengyel Iris L. Romero Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk Cell Reports |
author_facet |
Peter C. Hart Hilary A. Kenny Niklas Grassl Karen M. Watters Lacey M. Litchfield Fabian Coscia Ivana Blaženović Lisa Ploetzky Oliver Fiehn Matthias Mann Ernst Lengyel Iris L. Romero |
author_sort |
Peter C. Hart |
title |
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk |
title_short |
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk |
title_full |
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk |
title_fullStr |
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk |
title_full_unstemmed |
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk |
title_sort |
mesothelial cell hif1α expression is metabolically downregulated by metformin to prevent oncogenic tumor-stromal crosstalk |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-12-01 |
description |
Summary: The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin. : Hart et al. identify that the type 2 diabetes drug metformin inhibits ovarian cancer invasion by targeting crosstalk between cancer cells and adjacent normal stromal mesothelial cells, making the microenvironment less hospitable to cancer growth. Keywords: mesothelial cells, tumor microenvironment, ovarian cancer, metformin, HIF1, SUCLG2, IL-8, TGF, omental metastasis, succinate |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719315700 |
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