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Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells

Research output: Contribution to journalArticlepeer-review

Tony Ng, Thomas Eykyn, Rami Mustapha, Paul Barber, Ryan Green, Victoria Male, Gilbert Fruhwirth, Kevin M Brindle, Valentí Gomez, Fabian Flores-Borja, Fani Panagaki, Susana Ros

Original languageEnglish
Article numbereaax4585
Number of pages37
JournalScience Signaling
Volume13
Issue number652
DOIs
Accepted/In press26 Aug 2020
Published6 Oct 2020

Bibliographical note

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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Abstract

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.

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