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Lookup NU author(s): Dr Arian Laurence
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© 2018 American Society for Clinical Investigation.All right reserved. Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment, tumor-associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of the macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2–/– mice were more susceptible to tumor growth, with enhanced HIF-2α–mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2α but not HIF-1α for lysosome-mediated degradation. Blockade of HIF-2α transcriptional activity reversed the susceptibility of Atp6v0d2–/– mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2α was positively and negatively correlated with survival, respectively, suggesting a critical role of the macrophage lactate/ ATP6V0d2/HIF-2α axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth.
Author(s): Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, Wei Z, Xie X, Yin B, Chen F, Luo S, Liu H, Wang J, Jiang K, Gong F, Tang Z-H, Cheng X, Li H, Li Z, Laurence A, Wang G, Yang X-P
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2019
Volume: 129
Issue: 2
Pages: 631-646
Print publication date: 01/02/2019
Online publication date: 07/01/2019
Acceptance date: 13/11/2018
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/JCI123027
DOI: 10.1172/JCI123027
PubMed id: 30431439
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