Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma

Lan B. Hoang-Minh, Florian A. Siebzehnrubl, Changlin Yang, Silveli Suzuki-Hatano, Kyle Dajac, Tyler Loche, Nicholas Andrews, Michael Schmoll Massari, Jaimin Patel, Krisha Amin, Alvin Vuong, Ana Jimenez-Pascual, Paul Kubilis, Timothy J. Garrett, Craig Moneypenny, Christina A. Pacak, Jianping Huang, Elias J. Sayour, Duane A. Mitchell, Matthew R. SarkisianBrent A. Reynolds, Loic P. Deleyrolle

Research output: Contribution to journalArticlepeer-review

Abstract

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

Original languageEnglish (US)
Article numbere98772
JournalEMBO Journal
Volume37
Issue number23
DOIs
StatePublished - Dec 3 2018
Externally publishedYes

Bibliographical note

Funding Information:
Financial support was provided by American Brain Tumor Association Basic Research Fellowship Grant (L.H.M.), Tenovus Cancer Care TIG2015/L19 and the Cancer Research UK Cardiff Centre (F.A.S.), Preston A. Wells, Jr. Endowment 00107592 (J.H.), 1K08CA199224-01A1 (E.J.S.), American Cancer Society Research Scholar Grant RSG-13-031-01-DDC (M.R.S.), Preston A. Wells, Jr. Brain Tumor Research Fund (D.A.M.), NINDS R24 NS086554-01 (B.A.R.), American Cancer Society Chris DiMarco Institutional Research Grant, Accelerate Brain Cancer Cure, American Brain Tumor Association Research Grant DG1800014, and Preston A. Wells, Jr. Brain Tumor Research Fund (L.P.D.). This study was supported by the Robert P. Apkarian Integrated Electron Microscopy Core (RPAIEMC), which is subsidized by the Emory College of Arts and Sciences and the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. The authors would like to thank the University of Florida Interdisciplinary Center for Biotechnology Research Cytometry Core (N. Benson and A. Doty), the Cell & Tissue Analysis Core (D. Smith, NIH Grant # 1S10OD020026), M. Dajac and M. Andrews for technical assistance, the Florida Center for Brain Tumor Research (B. Frentzen, R. McTiernan, and J. Pittman) for access to brain tumor samples, and B. Tugertimur for his assistance in setting up the MTT assays.

Funding Information:
LBH-M, FAS, MRS, CAP, BAR, and LPD conceived and designed the research studies; LBH-M, FAS, CY, KD, TL, NA, MSM, JP, KA, AV, AJ-P, SS-H, CM, and LPD collected and/or assembled the data; LBH-M, FAS, CY, JH, EJS, TJG, DAM, SS-H, CAP, PK, MRS, BAR, and LPD analyzed and interpreted the data; LBH-M, FAS, EJS, and, LPD wrote the manuscript. FAS, DAM, MRS, BAR, and LPD provided financial support. All authors gave final approval of the manuscript.

Publisher Copyright:
© 2018 The Authors

Keywords

  • brain cancer
  • cancer stem cells
  • glioblastoma
  • metabolism
  • slow-cycling cells

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