Myeloid Cell-Derived Creatine in the Hypoxic Niche Promotes Glioblastoma Growth

Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and human GBM patients 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 GATM. Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). Therefore, we hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine can be 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.Funding Information: National Institutes of Health / NINDS grant 1R01NS115955-01 (MSL, JM); National Institutes of Health / NINDS grant P50CA221747 (MSL, JM) SPORE subaward; National Institutes of Health / NCI R35CA197532 (NSC).Declaration of Interests: Authors declare no competing interests.Ethics Approval Statement: All mouse protocols performed in this study were approved by Northwestern’s Institutional Animal Care and Use Committee under study approval number IS00017401.