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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Glioma | Research

GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression

Authors: Chaolong Yan, Zijiang Yang, Pin Chen, Yuyang Yeh, Chongjing Sun, Tao Xie, Wei Huang, Xiaobiao Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma.

Methods

Bioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo.

Results

Elevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo.

Conclusion

These findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.

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Wang D, et al. SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD. Clin Transl Med. 2020;10:e168. https://doi.org/10.1002/ctm2.168.CrossRefPubMedPubMedCentral

Pan Z, et al. EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Mol Cancer. 2022;21:16. https://doi.org/10.1186/s12943-021-01485-6.CrossRefPubMedPubMedCentral

Yabo YA, Niclou SP, Golebiewska A. Cancer cell heterogeneity and plasticity: a paradigm shift in glioblastoma. Neuro Oncol. 2021. https://doi.org/10.1093/neuonc/noab269.CrossRefPubMedCentral

Verhaak RGW, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110. https://doi.org/10.1016/j.ccr.2009.12.020.CrossRefPubMedPubMedCentral

Segerman A, et al. Clonal variation in drug and radiation response among glioma-initiating cells is linked to proneural-mesenchymal transition. Cell Rep. 2016;17:2994–3009. https://doi.org/10.1016/j.celrep.2016.11.056.CrossRefPubMed

Fedele M, Cerchia L, Pegoraro S, Sgarra R, Manfioletti G. Proneural-mesenchymal transition: phenotypic plasticity to acquire multitherapy resistance in glioblastoma. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20112746.

Feng R, et al. Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Commun Signal. 2018;16:54. https://doi.org/10.1186/s12964-018-0262-x.CrossRefPubMedPubMedCentral

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37. https://doi.org/10.1038/nm.3394.CrossRefPubMedPubMedCentral

Wang G, et al. Tumor-associated microglia and macrophages in glioblastoma: from basic insights to therapeutic opportunities. Front Immunol. 2022;13: 964898. https://doi.org/10.3389/fimmu.2022.964898.CrossRefPubMedPubMedCentral

10.

Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19:20–7. https://doi.org/10.1038/nn.4185.CrossRefPubMedPubMedCentral

11.

Neftel C, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178:835-849 e821. https://doi.org/10.1016/j.cell.2019.06.024.CrossRefPubMedPubMedCentral

12.

Murray PJ, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20. https://doi.org/10.1016/j.immuni.2014.06.008.CrossRefPubMedPubMedCentral

13.

Peng P, et al. TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling. Theranostics. 2022;12:4221–36. https://doi.org/10.7150/thno.69605.CrossRefPubMedPubMedCentral

14.

Gao X, et al. Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression. J Transl Med. 2023;21:53. https://doi.org/10.1186/s12967-023-03918-w.CrossRefPubMedPubMedCentral

15.

Zhang A, et al. Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics. 2021;11:3839–52. https://doi.org/10.7150/thno.53749.CrossRefPubMedPubMedCentral

16.

Yan J, et al. FGL2-wired macrophages secrete CXCL7 to regulate the stem-like functionality of glioma cells. Cancer Lett. 2021;506:83–94. https://doi.org/10.1016/j.canlet.2021.02.021.CrossRefPubMedPubMedCentral

17.

Mu X, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17:428–38. https://doi.org/10.1080/15384101.2018.1444305.CrossRefPubMedPubMedCentral

18.

Su S, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25:605–20. https://doi.org/10.1016/j.ccr.2014.03.021.CrossRefPubMed

19.

Colegio OR, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–63. https://doi.org/10.1038/nature13490.CrossRefPubMedPubMedCentral

20.

Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37. https://doi.org/10.1038/nrc3038.CrossRefPubMed

21.

Guyon J, et al. Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis. EMBO Mol Med. 2022;14:e15343. https://doi.org/10.15252/emmm.202115343.CrossRefPubMedPubMedCentral

22.

Chesnelong C, et al. Lactate dehydrogenase a silencing in IDH mutant gliomas. Neuro Oncol. 2014;16:686–95. https://doi.org/10.1093/neuonc/not243.CrossRefPubMed

23.

Silva LS, et al. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep. 2017;18:2172–85. https://doi.org/10.15252/embr.201744154.CrossRefPubMedPubMedCentral

24.

Miranda-Gonçalves V, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 2013;15:172–88. https://doi.org/10.1093/neuonc/nos298.CrossRefPubMed

25.

She X, et al. SETDB1 methylates MCT1 promoting tumor progression by enhancing the lactate shuttle. Adv Sci (Weinh). 2023:e2301871. https://doi.org/10.1002/advs.202301871.

26.

Sitter B, Forsmark A, Solheim O. Elevated serum lactate in glioma patients: associated factors. Front Oncol. 2022;12:831079. https://doi.org/10.3389/fonc.2022.831079.CrossRefPubMedPubMedCentral

27.

Maldonado F, et al. Association between preoperative serum lactate concentrate with tumor cell proliferative index in primary brain tumor. J Neurosurg Sci. 2022;66:91–5. https://doi.org/10.23736/S0390-5616.19.04715-5.CrossRefPubMed

28.

Branco M, et al. Serum lactate levels are associated with glioma malignancy grade. Clin Neurol Neurosurg. 2019;186: 105546. https://doi.org/10.1016/j.clineuro.2019.105546.CrossRefPubMed

29.

Bowman RL, Wang Q, Carro A, Verhaak RGW, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19:139–41. https://doi.org/10.1093/neuonc/now247.CrossRefPubMed

30.

Speir ML, et al. UCSC Cell Browser: visualize your single-cell data. Bioinformatics. 2021;37:4578–80. https://doi.org/10.1093/bioinformatics/btab503.CrossRefPubMedPubMedCentral

31.

Müller S, et al. A single-cell atlas of human glioblastoma reveals a single axis of phenotype in tumor-propagating cells. 2018. https://doi.org/10.1101/377606.

32.

Zhang Y, et al. Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis. Mol Cell. 2018;71:201-215 e207. https://doi.org/10.1016/j.molcel.2018.06.023.CrossRefPubMed

33.

Liu Q, et al. Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression. Int J Biol Sci. 2020;16:1023–34. https://doi.org/10.7150/ijbs.40535.CrossRefPubMedPubMedCentral

34.

Chen P, et al. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci USA. 2017;114:580–5. https://doi.org/10.1073/pnas.1614035114.CrossRefPubMedPubMedCentral

35.

Paolini L, et al. Lactic acidosis together with GM-CSF and M-CSF induces human macrophages toward an inflammatory protumor phenotype. Cancer Immunol Res. 2020;8:383–95. https://doi.org/10.1158/2326-6066.CIR-18-0749.CrossRefPubMed

36.

Colella B, Faienza ,Di Bartolomeo S. EMT regulation by autophagy: a new perspective in glioblastoma biology. Cancers (Basel). 2019;11. https://doi.org/10.3390/cancers11030312.

37.

Chen P, et al. Rab32 promotes glioblastoma migration and invasion via regulation of ERK/Drp1-mediated mitochondrial fission. Cell Death Dis. 2023;14:198. https://doi.org/10.1038/s41419-023-05721-3.CrossRefPubMedPubMedCentral

38.

Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 2020;206:107451. https://doi.org/10.1016/j.pharmthera.2019.107451.CrossRefPubMed

39.

Sisignano M, Fischer MJM, Geisslinger G. Proton-sensing GPCRs in health and disease. Cells. 2021;10. https://doi.org/10.3390/cells10082050.

40.

Wei C, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18:64. https://doi.org/10.1186/s12943-019-0976-4.CrossRefPubMedPubMedCentral

41.

Ahmed MB, Alghamdi AAA, Islam SU, Lee J-S, Lee Y-S. cAMP signaling in cancer: A PKA-CREB and EPAC-centric approach. Cells. 2022;11. https://doi.org/10.3390/cells11132020.

42.

Zhang H, Kong Q, Wang J, Jiang Y, Hua H. Complex roles of cAMP–PKA–CREB signaling in cancer. Exp Hematol Oncol. 2020;9. https://doi.org/10.1186/s40164-020-00191-1.

43.

Liu W, et al. Lactate modulates iron metabolism by binding soluble adenylyl cyclase. Cell Metab. 2023;35:1597-1612 e1596. https://doi.org/10.1016/j.cmet.2023.06.017.CrossRefPubMed

44.

Vaupel P, Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol. 2021;599:1745–57. https://doi.org/10.1113/JP278810.CrossRefPubMed

45.

Brooks GA. The science and translation of lactate shuttle theory. Cell Metab. 2018;27:757–85. https://doi.org/10.1016/j.cmet.2018.03.008.CrossRefPubMed

46.

Lin Y, Qi Y, Jiang M, Huang W, Li B. Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma. Int Immunopharmacol. 2023;124. https://doi.org/10.1016/j.intimp.2023.110972.

47.

Shan T, et al. M2TAM subsets altered by lactic acid promote Tcell apoptosis through the PDL1/PD1 pathway. Oncol Rep. 2020;44:1885–94. https://doi.org/10.3892/or.2020.7767.CrossRefPubMedPubMedCentral

48.

Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol. 2021;21:151–61. https://doi.org/10.1038/s41577-020-0406-2.CrossRefPubMed

49.

Ihara Y, et al. The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. Proc Natl Acad Sci U S A. 2010;107:17309–14. https://doi.org/10.1073/pnas.1001165107.CrossRefPubMedPubMedCentral

50.

Wang HX, et al. Overexpression of G-protein-coupled receptors 65 in glioblastoma predicts poor patient prognosis. Clin Neurol Neurosurg. 2018;164:132–7. https://doi.org/10.1016/j.clineuro.2017.11.017.CrossRefPubMed

Title: GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression
Authors: Chaolong Yan
Zijiang Yang
Pin Chen
Yuyang Yeh
Chongjing Sun
Tao Xie
Wei Huang
Xiaobiao Zhang
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Glioma
Glioma
Glioma
Glioblastoma
Glioblastoma
Glioblastoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-03025-8

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