Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression
Na Liu, … , Guoping Wang, Xiang-Ping Yang
Na Liu, … , Guoping Wang, Xiang-Ping Yang
Published February 1, 2019; First published November 15, 2018
Citation Information: J Clin Invest. 2019;129(2):631-646. https://doi.org/10.1172/JCI123027.
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Research Article Immunology Oncology

Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression

Abstract

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.

Authors

Na Liu, Jing Luo, Dong Kuang, Sanpeng Xu, Yaqi Duan, Yu Xia, Zhengping Wei, Xiuxiu Xie, Bingjiao Yin, Fang Chen, Shunqun Luo, Huicheng Liu, Jing Wang, Kan Jiang, Feili Gong, Zhao-hui Tang, Xiang Cheng, Huabin Li, Zhuoya Li, Arian Laurence, Guoping Wang, Xiang-Ping Yang

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Figure 5

Atp6v0d2 deficiency results in enhanced tumor angiogenesis.

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Atp6v0d2 deficiency results in enhanced tumor angiogenesis. (A–I) WT an...
(A–I) WT and Atp6v0d2–/– mice were injected s.c. with 5 × 105 LLC cells. On day 15 after inoculation, mice were sacrificed (n = 5). (A–C) Double immunostaining for CD31 (red) and α-SMA (green) vessels in tumor tissues from WT and Atp6v0d2–/– mice (A). Quantification of the percentage CD31+ vessels (B) and α-SMA+CD31+ vessels (C). (D and E) H&E staining on tumor tissues in WT and Atp6v0d2–/– mice. Histogram depicts the percentage of hemorrhagic area versus the whole tumor area (E). (F) Comparison of tumor tissue VEGF levels at day 15 in WT and Atp6v0d2–/– mice. (G and H) The expression of Vegf in tumor tissues (G) or isolated TAMs (H) from WT and Atp6v0d2–/– mice was determined by qRT-PCR. (I and J) Expression analysis of Vegf by qRT-PCR in WT and Atp6v0d2–/– BMDMs that were stimulated with LLC TCM (I) or B16-F10 TCM (J) for 6 hours. Data are representative of 3 independent experiments. Data were assessed by Student’s t test and are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 100 μm.