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

Cell Metab. 2023 Dec 14:S1550-4131(23)00445-X. doi: 10.1016/j.cmet.2023.11.013. Online ahead of print.ABSTRACTGlioblastoma (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.PMID:38134929 | DOI:10.1016/j.cmet.2023.11.013

Source: Cell Metabolism - December 22, 2023 Category: Cytology Authors: 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 Cas Source Type: research