Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Oct 14

PMID 36232951

Authors

Corinna Seliger

Anne-Louise Meyer

Verena Leidgens

Lisa Rauer

Sylvia Moeckel

Birgit Jachnik

Judith Proske

Katja Dettmer

Tanja Rothhammer-Hampl

Leon D Kaulen

Markus J Riemenschneider

Peter J Oefner

Marina Kreutz

Nils-Ole Schmidt

Marsha Merrill

Martin Uhl

Kathrin Renner

Arabel Vollmann-Zwerenz

Martin Proescholdt

Peter Hau

Affiliations

Soon will be listed here.

Abstract

Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.

Citing Articles

Insights into Metabolic Reprogramming in Tumor Evolution and Therapy.

Chiu C, Guerrero J, Regalado R, Zhou J, Zamora M, Notarte K Cancers (Basel). 2024; 16(20).

PMID: 39456607 PMC: 11506062. DOI: 10.3390/cancers16203513.

Glioma Stem Cells-Features for New Therapy Design.

Pecina-Slaus N, Hrascan R Cancers (Basel). 2024; 16(8).

PMID: 38672638 PMC: 11049195. DOI: 10.3390/cancers16081557.

Glioblastoma Therapy: Past, Present and Future.

Obrador E, Moreno-Murciano P, Oriol-Caballo M, Lopez-Blanch R, Pineda B, Gutierrez-Arroyo J Int J Mol Sci. 2024; 25(5).

PMID: 38473776 PMC: 10931797. DOI: 10.3390/ijms25052529.

Proneural-mesenchymal antagonism dominates the patterns of phenotypic heterogeneity in glioblastoma.

Bv H, Jolly M iScience. 2024; 27(3):109184.

PMID: 38433919 PMC: 10905000. DOI: 10.1016/j.isci.2024.109184.

Crosstalk between glioblastoma and tumor microenvironment drives proneural-mesenchymal transition through ligand-receptor interactions.

Lai Y, Lu X, Liao Y, Ouyang P, Wang H, Zhang X Genes Dis. 2023; 11(2):874-889.

PMID: 37692522 PMC: 10491977. DOI: 10.1016/j.gendis.2023.05.025.

References

Lai M, Vassallo I, Lanz B, Poitry-Yamate C, Hamou M, Cudalbu C . In vivo characterization of brain metabolism by H MRS, C MRS and FDG PET reveals significant glucose oxidation of invasively growing glioma cells. Int J Cancer. 2018; 143(1):127-138. DOI: 10.1002/ijc.31299. View

Leidgens V, Proske J, Rauer L, Moeckel S, Renner K, Bogdahn U . Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation. Oncotarget. 2016; 8(5):8250-8263. PMC: 5352398. DOI: 10.18632/oncotarget.14159. View

Smyth G, Michaud J, Scott H . Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics. 2005; 21(9):2067-75. DOI: 10.1093/bioinformatics/bti270. View

Welch M, Grommes C . Retrospective analysis of the effects of steroid therapy and antidiabetic medication on survival in diabetic glioblastoma patients. CNS Oncol. 2014; 2(3):237-46. PMC: 6166491. DOI: 10.2217/cns.13.12. View

Seliger C, Luber C, Gerken M, Schaertl J, Proescholdt M, Riemenschneider M . Use of metformin and survival of patients with high-grade glioma. Int J Cancer. 2018; 144(2):273-280. DOI: 10.1002/ijc.31783. View

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L . Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2018; 33(1):152. PMC: 5892424. DOI: 10.1016/j.ccell.2017.12.012. View

Seliger C, Genbrugge E, Gorlia T, Chinot O, Stupp R, Nabors B . Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. Int J Cancer. 2019; 146(3):803-809. DOI: 10.1002/ijc.32337. View

Voss D, Spina R, Carter D, Lim K, Jeffery C, Bar E . Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression. Sci Rep. 2017; 7(1):4292. PMC: 5487345. DOI: 10.1038/s41598-017-04612-w. View

Schulze M, Sommer A, Plotz S, Farrell M, Winner B, Grosch J . Sporadic Parkinson's disease derived neuronal cells show disease-specific mRNA and small RNA signatures with abundant deregulation of piRNAs. Acta Neuropathol Commun. 2018; 6(1):58. PMC: 6038190. DOI: 10.1186/s40478-018-0561-x. View

10.

Cuyas E, Fernandez-Arroyo S, Corominas-Faja B, Rodriguez-Gallego E, Bosch-Barrera J, Martin-Castillo B . Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget. 2015; 6(14):12279-96. PMC: 4494938. DOI: 10.18632/oncotarget.3733. View

11.

Oizel K, Chauvin C, Oliver L, Gratas C, Geraldo F, Jarry U . Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity. Clin Cancer Res. 2017; 23(20):6292-6304. DOI: 10.1158/1078-0432.CCR-16-3102. View

12.

Verhaak R, Hoadley K, Purdom E, Wang V, Qi Y, Wilkerson M . Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010; 17(1):98-110. PMC: 2818769. DOI: 10.1016/j.ccr.2009.12.020. View

13.

Keunen O, Johansson M, Oudin A, Sanzey M, Abdul Rahim S, Fack F . Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A. 2011; 108(9):3749-54. PMC: 3048093. DOI: 10.1073/pnas.1014480108. View

14.

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View

15.

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(11). PMC: 6600373. DOI: 10.3390/ijms20112746. View

16.

Heinrich P, Kohler C, Ellmann L, Kuerner P, Spang R, Oefner P . Correcting for natural isotope abundance and tracer impurity in MS-, MS/MS- and high-resolution-multiple-tracer-data from stable isotope labeling experiments with IsoCorrectoR. Sci Rep. 2018; 8(1):17910. PMC: 6297158. DOI: 10.1038/s41598-018-36293-4. View

17.

Lei Y, Yi Y, Liu Y, Liu X, Keller E, Qian C . Metformin targets multiple signaling pathways in cancer. Chin J Cancer. 2017; 36(1):17. PMC: 5270304. DOI: 10.1186/s40880-017-0184-9. View

18.

Jin L, Zhou Y . Crucial role of the pentose phosphate pathway in malignant tumors. Oncol Lett. 2019; 17(5):4213-4221. PMC: 6444344. DOI: 10.3892/ol.2019.10112. View

19.

Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K . Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med. 2012; 1(11):811-24. PMC: 3659661. DOI: 10.5966/sctm.2012-0058. View

20.

Fayzullin A, Sandberg C, Spreadbury M, Saberniak B, Grieg Z, Skaga E . Phenotypic and Expressional Heterogeneity in the Invasive Glioma Cells. Transl Oncol. 2018; 12(1):122-133. PMC: 6172486. DOI: 10.1016/j.tranon.2018.09.014. View