美国西北大学Jason Miska团队近期取得重要工作进展，他们研究发现，骨髓细胞来源的肌酸在缺氧环境中能够促进胶质母细胞瘤的生长。相关研究结果2023年12月21日在线发表于《细胞—代谢》杂志上。

据介绍，胶质母细胞瘤（GBM）是一种以肿瘤相关髓系细胞（TAMC）浸润为主的恶性肿瘤。

对小鼠模型和GBM患者的TAMC代谢表型的检查表明，从头肌酸代谢途径是TAMC的标志。多组学分析显示，TAMC包围GBM缺氧坏死周围区域，并表达肌酸代谢酶甘氨酸氨基转移酶（GATM）。相反，位于这些相同区域内的GBM细胞在表达肌酸转运蛋白（SLC6A8）方面具有独特的特异性。研究人员假设TAMC为肿瘤提供肌酸，促进GBM的进展。

同位素示踪显示TAMC分泌的肌酸被肿瘤细胞吸收。补充肌酸可保护肿瘤免受缺氧诱导的应激，而SLC6A8的基因消融或药理学抑制可消除这种应激。最后，使用临床相关化合物RGX-202-01抑制肌酸转运，减缓肿瘤生长并增强体内放射治疗。

总之，这项工作强调了肌酸从骨髓到肿瘤的转移促进了缺氧微环境中的肿瘤生长。

附：英文原文

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

Author: 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 McCortney, Jordain 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

Issue&Volume: 2023-12-21

Abstract: Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associatedmyeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models andpatients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealedthat TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatinemetabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells locatedwithin 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 abrogatedwith genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition ofcreatine transport using the clinically relevant compound, RGX-202-01, blunted tumorgrowth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growthin the hypoxic niche.

DOI: 10.1016/j.cmet.2023.11.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00445-X