Hypoxia-induced one-carbon metabolic reprogramming in glioma stem-like cells

Abstract

Glioma stem cells (GSCs) in the hypoxic niches contribute to tumor initiation, progression, and recurrence in glioblastoma (GBM). Metabolic pathways are altered in GSCs under hypoxia, but the mechanism underlying the altered one-carbon metabolism in GSCs by hypoxia is largely unknown. Here, we report that hypoxia induces down-regulation of DHFR as well as up-regulation of MAT2A in GBM tumorsphere cells, and confers them the ability of cell proliferation that is independent of exogenous folate. Importantly, short-term inhibition of the methionine cycle or exposure to the MAT2A inhibitor is sufficient to cripple the tumor-initiating capability of GBM tumorsphere cells. Therefore, we present a novel perspective on how hypoxia alters the pattern of one-carbon metabolism in GBM tumorsphere cells and provide evidence that restriction of methionine intake or targeting MAT2A inhibits the tumorigenicity of GBM tumorsphere cells.

Keywords

glioblastoma / hypoxia / DHFR / MAT2A / tumorigenicity

References

[1] Zhang Q, Zheng J, Wu W, et al. TRIM56 acts through the IQGAP1-CDC42 signaling axis to promote glioma cell migration and invasion. Cell Death Dis 2023;14:178.

[2] Lin W, Niu R, Park SM, et al. IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis. Nat Commun 2023;14:1578.

[3] Muthukrishnan SD, Kawaguchi R, Nair P, et al. P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells. Nat Commun 2022;13:6202.

[4] Mohammadali F, Abroun S, Atashi A. Mild hypoxia and human bone marrow mesenchymal stem cells synergistically enhance expansion and homing capacity of human cord blood CD34+ stem cells. Iran J Basic Med Sci 2018;21:709–16.

[5] Gassmann M, Fandrey J, Bichet S, et al. Oxygen supply and oxygen- dependent gene expression in differentiating embryonic stem cells. Proc Natl Acad Sci USA 1996;93:2867–72.

[6] Kashiwagi T, Takazawa Y, Kagawa T, et al. Organization of self- advantageous niche by neural stem/progenitor cells during development via autocrine VEGF-A under hypoxia. Inflamm Regen 2023;43:8.

[7] Kandarakov O, Belyavsky A, Semenova E. Bone marrow niches of hematopoietic stem and progenitor cells. Int J Mol Sci 2022;23:4462.

[8] Douyere M, Gong C, Richard M, et al. NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells. Cancer Cell Int 2022;22:377.

[9] Zhou X, Li C, Chen T, et al. Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy. Mol Cancer 2023;22:36.

[10] Wang P, Gong S, Liao B, et al. HIF1alpha/HIF2alpha induces glioma cell dedifferentiation into cancer stem cells through Sox2 under hypoxic conditions. J Cancer 2022;13:1–14.

[11] Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009;15:501–13.

[12] Seidel S, Garvalov BK, Wirta V, et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 2010;133:983–95.

[13] Semenza GL. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol Aspects Med 2016;47-48:15–23.

[14] Stegen S, Laperre K, Eelen G, et al. HIF-1alpha metabolically controls collagen synthesis and modification in chondrocytes. Nature 2019;565:511–5.

[15] Zhang A, Huang Z, Tao W, et al. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J 2022;41:e109187.

[16] Liu K, Jiang L, Shi Y, et al. Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation. Cell Death Differ 2022;29:1834–49.

[17] Harmati M, Bukva M, Boroczky T, et al. The role of the metabolite cargo of extracellular vesicles in tumor progression. Cancer Metastasis Rev 2021;40:1203–21.

[18] Niu X, Stancliffe E, Gelman SJ, et al. Cytosolic and mitochondrial NADPH fluxes are independently regulated. Nat Chem Biol 2023;19:837–45.

[19] Korimerla N, Wahl DR. Interactions between radiation and one- carbon metabolism. Int J Mol Sci 2022;23:1919.

[20] Nilsson R, Jain M, Madhusudhan N, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun 2014;5:3128.

[21] Sullivan MR, Darnell AM, Reilly MF, et al. Methionine synthase is essential for cancer cell proliferation in physiological folate environments. Nat Metab 2021;3:1500–11.

[22] Wang Z, Yip LY, Lee JHJ, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25:825–37.

[23] Villa E, Sahu U, O’Hara BP, et al. mTORC1 stimulates cell growth through SAM synthesis and m(6)A mRNA-dependent control of protein synthesis. Mol Cell 2021;81:2076–2093.e9.

[24] Li JT, Yang H, Lei MZ, et al. Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA. Signal Transduct Target Ther 2022;7:192.

[25] McIntyre A, Patiar S, Wigfield S, et al. Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin Cancer Res 2012;18:3100–11.

[26] Zanoni M, Cortesi M, Zamagni A, et al. Modeling neoplastic disease with spheroids and organoids. J Hematol Oncol 2020;13:97.

[27] Smalley KS, Lioni M, Noma K, et al. In vitro three-dimensional tumor microenvironment models for anticancer drug discovery. Expert Opin Drug Discov 2008;3:1–10.

[28] Lu H, Stenzel MH. Multicellular tumor spheroids (MCTS) as a 3D in vitro evaluation tool of nanoparticles. Small 2018;14:e1702858.

[29] Ohnishi K, Tani T, Bando S, et al. Plastic induction of CD133AC133-positive cells in the microenvironment of glioblastoma spheroids. Int J Oncol 2014;45:581–6.

[30] Fawal MA, Jungas T, Kischel A, et al. Cross talk between one-carbon metabolism, Eph signaling, and histone methylation promotes neural stem cell differentiation. Cell Rep 2018;23:2864–2873.e7.

[31] Bonavia R, Inda MD, Cavenee WK, et al. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res 2011;71:4055–60.

[32] Masui K, Onizuka H, Cavenee WK, et al. Metabolic reprogramming in the pathogenesis of glioma: update. Neuropathology 2019;39:3–13.

[33] Agnihotri S, Zadeh G. Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions. Neuro-Oncology 2016;18:160–72.

[34] Sun LC, Zhang HF, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein ↦ Cell 2022;13:877–919.

[35] Zarou MM, Vazquez A, Helgason GV. Folate metabolism: a re-emerging therapeutic target in haematological cancers. Leukemia 2021;35:1539–51.

[36] Pieroth R, Paver S, Day S, et al. Folate and its impact on cancer risk. Curr Nutr Rep 2018;7:70–84.

[37] Zgheib R, Battaglia-Hsu SF, Hergalant S, et al. Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency. Cell Death Dis 2019;10:596.

[38] Fawal MA, Jungas T, Davy A. Inhibition of DHFR targets the self-renewing potential of brain tumor initiating cells. Cancer Lett 2021;503:129–37.

[39] Todaro M, Alea MP, Di Stefano AB, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 2007;1:389–402.

[40] Liang BC. Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J Neurooncol 1996;29:149–55.

[41] Semenza GL. Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell 2004;5:405–6.

[42] Chi JT, Wang Z, Nuyten DS, et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 2006;3:e47.

[43] Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007;26:225–39.

[44] Sathornsumetee S, Cao Y, Marcello JE, et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 2008;26:271–8.

[45] Cowman SJ, Koh MY. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer 2022;8:28–42.

[46] Infantino V, Santarsiero A, Convertini P, et al. Cancer cell metabolism in hypoxia: role of HIF-1 as key regulator and therapeutic target. Int J Mol Sci 2021;22:5703.

[47] Grimes DR, Jansen M, Macauley RJ, et al. Evidence for hypoxia increasing the tempo of evolution in glioblastoma. Br J Cancer 2020;123:1562–9.

[48] Domenech M, Hernandez A, Plaja A, et al. Hypoxia: the cornerstone of glioblastoma. Int J Mol Sci 2021;22:12608.

[49] Gabriely G, Wheeler MA, Takenaka MC, et al. Role of AHR and HIF-1alpha in glioblastoma metabolism. Trends Endocrinol Metab 2017;28:428–36.

[50] Sonam Takkar VS, Ghosh S, Suri A, et al. Hypoxia-inducible miR-196a modulates glioblastoma cellproliferation and migration through complex regulation of NRAS. Cell Oncol 2021;44: 433–51.

[51] Xiong M, Wang P, Pan B, et al. The diagnostic and prognostic values of microRNA-196a in cancer. Biosci Rep 2021;41:BSR20203559.

[52] Ye J, Fan J, Venneti S, et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 2014;4:1406–17.

[53] Li AM, Ducker GS, Li Y, et al. Metabolic profiling reveals a dependency of human metastatic breast cancer on mitochondrial serine and one-carbon unit metabolism. Mol Cancer Res 2020;18:599–611.

[54] Orentreich N, Matias JR, DeFelice A, et al. Low methionine ingestion by rats extends life span. J Nutr 1993;123:269–74.

[55] Wu G, Xu J, Wang Q, et al. Methionine-restricted diet: a feasible strategy against chronic or aging-related diseases. J Agric Food Chem 2023;71:5–19.

[56] Zou K, Rouskin S, Dervishi K, et al. Life span extension by glucose restriction is abrogated by methionine supplementation: cross-talk between glucose and methionine and implication of methionine as a key regulator of life span. Sci Adv 2020;6:eaba1306.

[57] Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9:391–403.

[58] Liu C, Teng ZQ, Santistevan NJ, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 2010;6:433–44.

[59] Cheng Y, Wang ZM, Tan W, et al. Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci 2018;21:1689–703.

[60] He XC, Wang J, Du HZ, et al. Intranasal administration of Agomirlet-7i improves cognitive function in mice with traumatic brain injury. Cells 2022;11:3253.

[61] Zhou W, Ke SQ, Huang Z, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 2015;17:170–82.

[62] Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 2013;153:139–52.

[63] Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756–60.

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2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.