Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth

Aida Rashidi, Leah K. Billingham, Andrew Zolp, Tzu yi Chia, Caylee Silvers, Joshua L. Katz, Cheol H. Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M. Markwell, Crismita Dmello, Victor A. Arrieta, Kaylee Zilinger, Irene M. Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M. Steffens, Kathleen McCortneyJordain P. Walshon, Mariah S. Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U. Ahmed, Daniel J. Brat, Dieter H. Heiland, Catalina Lee-Chang, Maciej S. Lesniak, Navdeep S. Chandel, Jason Miska*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.

Original languageEnglish (US)
Pages (from-to)62-77.e8
JournalCell Metabolism
Volume36
Issue number1
DOIs
StatePublished - Jan 2 2024

Keywords

  • creatine metabolism
  • glioblastoma
  • myeloid cells
  • pseudopalisading necrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth'. Together they form a unique fingerprint.

Cite this