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 7

Suppression of HIF-2α activity reverses the enhanced tumorigenesis in Atp6v0d2–/– mice.

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Suppression of HIF-2α activity reverses the enhanced tumorigenesis in At...
(A–J) WT and Atp6v0d2–/– mice (n = 5) were injected s.c. with 5 × 105 LLC cells. Once the tumor volumes reached 100–200 mm3 at around day 10, mice were gavaged with vehicle or HIF-2α inhibitor PT2385 (5 mg/kg) twice daily for 4 consecutive days. Growth curve (A) and tumor weight (B) were plotted. (C) Comparison of tumor tissue VEGF levels. (D–F) Immunostaining of CD31 and α-SMA in tumor tissues (D) and quantification of CD31+ area percentage (E), CD31+α-SMA+ vessels as a percentage of CD31+ vessels (F) in the tumor areas. (G–J) qRT-PCR analysis of M2 marker genes Mrc1 (G), Arg1 (H), Fizz1 (I), Ym1 (J) in the tumor tissues. (K–M) WT and Atp6v0d2–/– BMDMs were stimulated with LLC TCM for 24 hours with or without PT2385 (20 mM) and PT2385 was added 18 hours prior to the TCM stimulation. Expression of Arg1 (K), Fizz1 (L), and Ym1 (M) was determined by qRT-PCR. Data were assessed by 1-way ANOVA with Dunnett’s test and are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 100 μm.