Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk

Research output: Contribution to journal › Journal article › Research › peer-review

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Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk. / Hart, Peter C; Kenny, Hilary A; Grassl, Niklas; Watters, Karen M; Litchfield, Lacey M; Coscia, Fabian; Blaženović, Ivana; Ploetzky, Lisa; Fiehn, Oliver; Mann, Matthias; Lengyel, Ernst; Romero, Iris L.

In: Cell Reports, Vol. 29, No. 12, 2019, p. 4086-4098.e6.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hart, PC, Kenny, HA, Grassl, N, Watters, KM, Litchfield, LM, Coscia, F, Blaženović, I, Ploetzky, L, Fiehn, O, Mann, M, Lengyel, E & Romero, IL 2019, 'Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk', Cell Reports, vol. 29, no. 12, pp. 4086-4098.e6. https://doi.org/10.1016/j.celrep.2019.11.079

APA

Hart, P. C., Kenny, H. A., Grassl, N., Watters, K. M., Litchfield, L. M., Coscia, F., Blaženović, I., Ploetzky, L., Fiehn, O., Mann, M., Lengyel, E., & Romero, I. L. (2019). Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk. Cell Reports, 29(12), 4086-4098.e6. https://doi.org/10.1016/j.celrep.2019.11.079

Vancouver

Hart PC, Kenny HA, Grassl N, Watters KM, Litchfield LM, Coscia F et al. Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk. Cell Reports. 2019;29(12):4086-4098.e6. https://doi.org/10.1016/j.celrep.2019.11.079

Author

Hart, Peter C ; Kenny, Hilary A ; Grassl, Niklas ; Watters, Karen M ; Litchfield, Lacey M ; Coscia, Fabian ; Blaženović, Ivana ; Ploetzky, Lisa ; Fiehn, Oliver ; Mann, Matthias ; Lengyel, Ernst ; Romero, Iris L. / Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk. In: Cell Reports. 2019 ; Vol. 29, No. 12. pp. 4086-4098.e6.

Bibtex

@article{c5655e253fb64bdc82dc8b22a0268b53,
title = "Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk",
abstract = "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.",
author = "Hart, {Peter C} and Kenny, {Hilary A} and Niklas Grassl and Watters, {Karen M} and Litchfield, {Lacey M} and Fabian Coscia and Ivana Bla{\v z}enovi{\'c} and Lisa Ploetzky and Oliver Fiehn and Matthias Mann and Ernst Lengyel and Romero, {Iris L}",
note = "Copyright {\textcopyright} 2019 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2019",
doi = "10.1016/j.celrep.2019.11.079",
language = "English",
volume = "29",
pages = "4086--4098.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",

}

RIS

TY - JOUR

T1 - Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk

AU - Hart, Peter C

AU - Kenny, Hilary A

AU - Grassl, Niklas

AU - Watters, Karen M

AU - Litchfield, Lacey M

AU - Coscia, Fabian

AU - Blaženović, Ivana

AU - Ploetzky, Lisa

AU - Fiehn, Oliver

AU - Mann, Matthias

AU - Lengyel, Ernst

AU - Romero, Iris L

N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2019.11.079

DO - 10.1016/j.celrep.2019.11.079

M3 - Journal article

C2 - 31851935

VL - 29

SP - 4086-4098.e6

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 12

ER -

ID: 239207989