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 language | English (US) |
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Pages (from-to) | 62-77.e8 |
Journal | Cell Metabolism |
Volume | 36 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2 2024 |
Funding
This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). We would like to thank Prof. Ben-Sahra (Northwestern) for his assistance in the development and analyses of 13C-flux studies. We would also like to thank Isabel Kurth and Inspirna for both RGX-202-01 and continuous advice and guidance on this project. We would also like to thank Ting Xiao who consulted on and verified the statistical analyses in this work. We would also like to thank Peng Gao for his Metabolomics services which were performed at the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We would also like to thank Cheryl Olson, Alicia Steffens, and Katy McCortney for their expertise in immunostaining they performed as part of the Northwestern Nervous System Tumor Bank. This tissue bank is supported by the P50CA221747 SPORE for Translational Approaches to Brain Cancer. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Funding: National Institutes of Health/NINDS grant 1R01NS115955-01 (M.S.L. and J.M.), National Institutes of Health/NCI grant (J.M.) - 1R01CA279686-01, National Institutes of Health/NINDS grant P50CA221747 (M.S.L. and J.M.) SPORE subaward, National Institutes of Health/NCI R35CA197532 (N.S.C.), National Institutes of Health/R01NS096376-06A1, and 1R01CA223547-01. Conceptualization, J.M. C.L.-C. N.S.C. D.H.H. D.J.B. A.U.A. and M.S.L.; methodology, J.M. A.Z. A.L.-R. C.H.P. L.K.B. L.B. T.-y.C. I.M.J. P.Z. S.M.M. B.C. D.H. J.L.K. C.H.P. Y.G. C.S. S.D. C.D. J.P.W. A.M.S. K.M. M.S.F. H.L. and H.W.; scRNA-seq analysis: J.Z.; spatial metabolomics and transcriptomics, D.H.H.; animal breeding, A.L.-R.; neuropathologist, D.J.B.; multiplexed imaging analysis, V.A.A. in conjunction with the immunotherapy, assessment core at Northwestern University; supervision, J.M. N.S.C. M.S.L. C.L.-C. and D.J.B.; writing – original draft, J.M.M. N.S.C. A.R. A.Z. and L.K.B.; writing – review & editing, all authors. The authors declare no competing interests. This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553 ). We would like to thank Prof. Ben-Sahra (Northwestern) for his assistance in the development and analyses of 13 C-flux studies. We would also like to thank Isabel Kurth and Inspirna for both RGX-202-01 and continuous advice and guidance on this project. We would also like to thank Ting Xiao who consulted on and verified the statistical analyses in this work. We would also like to thank Peng Gao for his Metabolomics services which were performed at the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We would also like to thank Cheryl Olson, Alicia Steffens, and Katy McCortney for their expertise in immunostaining they performed as part of the Northwestern Nervous System Tumor Bank . This tissue bank is supported by the P50CA221747 SPORE for Translational Approaches to Brain Cancer . Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Funding: National Institutes of Health/NINDS grant 1R01NS115955-01 (M.S.L. and J.M.), National Institutes of Health/NCI grant (J.M.) - 1R01CA279686-01 , National Institutes of Health/NINDS grant P50CA221747 (M.S.L. and J.M.) SPORE subaward, National Institutes of Health/NCI R35CA197532 (N.S.C.), National Institutes of Health / R01NS096376-06A1 , and 1R01CA223547-01 .
Keywords
- creatine metabolism
- glioblastoma
- myeloid cells
- pseudopalisading necrosis
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology