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Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth
Cell Metabolism ( IF 27.7 ) Pub Date : 2023-12-21 , DOI: 10.1016/j.cmet.2023.11.013 Aida Rashidi 1 , Leah K Billingham 1 , Andrew Zolp 1 , Tzu-Yi Chia 1 , Caylee Silvers 1 , Joshua L Katz 1 , Cheol H Park 1 , Suzi Delay 1 , Lauren Boland 2 , Yuheng Geng 1 , Steven M Markwell 3 , Crismita Dmello 1 , Victor A Arrieta 1 , Kaylee Zilinger 1 , Irene M Jacob 1 , Aurora Lopez-Rosas 1 , David Hou 1 , Brandyn Castro 1 , Alicia M Steffens 1 , Kathleen McCortney 1 , Jordain P Walshon 1 , Mariah S Flowers 1 , Hanchen Lin 1 , Hanxiang Wang 1 , Junfei Zhao 4 , Adam Sonabend 1 , Peng Zhang 1 , Atique U Ahmed 1 , Daniel J Brat 3 , Dieter H Heiland 5 , Catalina Lee-Chang 1 , Maciej S Lesniak 1 , Navdeep S Chandel 6 , Jason Miska 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2023-12-21 , DOI: 10.1016/j.cmet.2023.11.013 Aida Rashidi 1 , Leah K Billingham 1 , Andrew Zolp 1 , Tzu-Yi Chia 1 , Caylee Silvers 1 , Joshua L Katz 1 , Cheol H Park 1 , Suzi Delay 1 , Lauren Boland 2 , Yuheng Geng 1 , Steven M Markwell 3 , Crismita Dmello 1 , Victor A Arrieta 1 , Kaylee Zilinger 1 , Irene M Jacob 1 , Aurora Lopez-Rosas 1 , David Hou 1 , Brandyn Castro 1 , Alicia M Steffens 1 , Kathleen McCortney 1 , Jordain P Walshon 1 , Mariah S Flowers 1 , Hanchen Lin 1 , Hanxiang Wang 1 , Junfei Zhao 4 , Adam Sonabend 1 , Peng Zhang 1 , Atique U Ahmed 1 , Daniel J Brat 3 , Dieter H Heiland 5 , Catalina Lee-Chang 1 , Maciej S Lesniak 1 , Navdeep S Chandel 6 , Jason Miska 1
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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 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 . This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
中文翻译：
缺氧环境中骨髓细胞来源的肌酸促进胶质母细胞瘤生长
胶质母细胞瘤（GBM）是一种以肿瘤相关骨髓细胞（TAMC）浸润为主的恶性肿瘤。对小鼠模型和 GBM 患者 TAMC 代谢表型的检查发现肌酸代谢途径是 TAMC 的标志。多组学分析表明，TAMC 围绕 GBM 的缺氧坏死周围区域，并表达肌酸代谢酶甘氨酸脒基转移酶 (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。我们假设 TAMC 为肿瘤提供肌酸，促进 GBM 进展。同位素示踪表明 TAMC 分泌的肌酸被肿瘤细胞吸收。补充肌酸可以保护肿瘤免受缺氧引起的应激，这种应激可以通过基因消融或 SLC6A8 的药物抑制来消除。最后，使用临床相关化合物 RGX-202-01 抑制肌酸转运，抑制肿瘤生长并增强放射治疗。这项工作强调肌酸从骨髓到肿瘤的转移促进缺氧环境中的肿瘤生长。
更新日期：2023-12-21
中文翻译：
缺氧环境中骨髓细胞来源的肌酸促进胶质母细胞瘤生长
胶质母细胞瘤（GBM）是一种以肿瘤相关骨髓细胞（TAMC）浸润为主的恶性肿瘤。对小鼠模型和 GBM 患者 TAMC 代谢表型的检查发现肌酸代谢途径是 TAMC 的标志。多组学分析表明，TAMC 围绕 GBM 的缺氧坏死周围区域，并表达肌酸代谢酶甘氨酸脒基转移酶 (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。我们假设 TAMC 为肿瘤提供肌酸，促进 GBM 进展。同位素示踪表明 TAMC 分泌的肌酸被肿瘤细胞吸收。补充肌酸可以保护肿瘤免受缺氧引起的应激，这种应激可以通过基因消融或 SLC6A8 的药物抑制来消除。最后，使用临床相关化合物 RGX-202-01 抑制肌酸转运，抑制肿瘤生长并增强放射治疗。这项工作强调肌酸从骨髓到肿瘤的转移促进缺氧环境中的肿瘤生长。
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