Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity.
Core genes
Glioma
Immunotherapy sensitivity
Nicotinamide metabolism
Prognosis
Tryptophan metabolism
Journal
BMC neurology
ISSN: 1471-2377
Titre abrégé: BMC Neurol
Pays: England
ID NLM: 100968555
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
18
06
2024
accepted:
18
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Nicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas. Bulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments. The high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228. Our study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.
Sections du résumé
BACKGROUND
BACKGROUND
Nicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas.
METHODS
METHODS
Bulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments.
RESULTS
RESULTS
The high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228.
CONCLUSIONS
CONCLUSIONS
Our study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.
Identifiants
pubmed: 39468708
doi: 10.1186/s12883-024-03924-5
pii: 10.1186/s12883-024-03924-5
doi:
Substances chimiques
Tryptophan
8DUH1N11BX
Niacinamide
25X51I8RD4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
419Informations de copyright
© 2024. The Author(s).
Références
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–51.
pubmed: 34185076
pmcid: 8328013
doi: 10.1093/neuonc/noab106
Bush NA, Chang SM, Berger MS. Current and future strategies for treatment of glioma. Neurosurg Rev. 2017;40(1):1–14.
pubmed: 27085859
doi: 10.1007/s10143-016-0709-8
Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin cancer Research: Official J Am Association Cancer Res. 2014;20(20):5290–301.
doi: 10.1158/1078-0432.CCR-14-0514
Ladomersky E, Zhai L, Lenzen A, Lauing KL, Qian J, Scholtens DM, et al. IDO1 inhibition synergizes with Radiation and PD-1 blockade to Durably Increase Survival against Advanced Glioblastoma. Clin cancer Research: Official J Am Association Cancer Res. 2018;24(11):2559–73.
doi: 10.1158/1078-0432.CCR-17-3573
Navas LE, Carnero A. NAD(+) metabolism, stemness, the immune response, and cancer. Signal Transduct Target Therapy. 2021;6(1):2.
doi: 10.1038/s41392-020-00354-w
Gasperi V, Sibilano M, Savini I, Catani MV. Niacin in the Central Nervous System: an update of Biological aspects and clinical applications. Int J Mol Sci. 2019;20(4).
Jung M, Lee KM, Im Y, Seok SH, Chung H, Kim DY, et al. Nicotinamide (niacin) supplement increases lipid metabolism and ROS-induced energy disruption in triple-negative breast cancer: potential for drug repositioning as an anti-tumor agent. Mol Oncol. 2022;16(9):1795–815.
pubmed: 35278276
pmcid: 9067146
doi: 10.1002/1878-0261.13209
Lv H, Lv G, Chen C, Zong Q, Jiang G, Ye D, et al. NAD(+) metabolism maintains inducible PD-L1 expression to Drive Tumor Immune Evasion. Cell Metabol. 2021;33(1):110–e275.
doi: 10.1016/j.cmet.2020.10.021
Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A phase 3 Randomized Trial of Nicotinamide for skin-Cancer chemoprevention. N Engl J Med. 2015;373(17):1618–26.
pubmed: 26488693
doi: 10.1056/NEJMoa1506197
Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discovery. 2019;18(5):379–401.
pubmed: 30760888
doi: 10.1038/s41573-019-0016-5
Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for Cancer Immunotherapy - challenges and opportunities. Trends Pharmacol Sci. 2018;39(3):307–25.
pubmed: 29254698
doi: 10.1016/j.tips.2017.11.007
Peyraud F, Guegan JP, Bodet D, Cousin S, Bessede A, Italiano A. Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: challenges and perspectives. Front Immunol. 2022;13:807271.
pubmed: 35173722
pmcid: 8841724
doi: 10.3389/fimmu.2022.807271
Liu H, Xiang Y, Zong QB, Dai ZT, Wu H, Zhang HM et al. TDO2 modulates liver cancer cell migration and invasion via the Wnt5a pathway. Int J Oncol. 2022;60(6).
Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, et al. Characterization of the selective indoleamine 2,3-Dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy. Mol Cancer Ther. 2018;17(12):2530–42.
pubmed: 30232146
doi: 10.1158/1535-7163.MCT-17-1104
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, et al. Phase I study of the indoleamine 2,3-Dioxygenase 1 (IDO1) inhibitor Navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in Advanced Solid tumors. Clin cancer Research: Official J Am Association Cancer Res. 2019;25(11):3220–8.
doi: 10.1158/1078-0432.CCR-18-2740
Du B, Shim JS. Targeting epithelial-mesenchymal transition (EMT) to Overcome Drug Resistance in Cancer. Molecules. 2016;21(7).
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–20.
pubmed: 27157931
doi: 10.1007/s00401-016-1545-1
Puchalski RB, Shah N, Miller J, Dalley R, Nomura SR, Yoon JG, et al. An anatomic transcriptional atlas of human glioblastoma. Sci (New York NY). 2018;360(6389):660–3.
doi: 10.1126/science.aaf2666
Lopez-Mejia IC, Pijuan J, Navaridas R, Santacana M, Gatius S, Velasco A, et al. Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness. Mol Oncol. 2023;17(1):98–118.
pubmed: 36409196
doi: 10.1002/1878-0261.13346
Shen W, Song Z, Zhong X, Huang M, Shen D, Gao P et al. Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform. iMeta. 2022;1(3).
Chuang HH, Zhen YY, Tsai YC, Chuang CH, Hsiao M, Huang MS et al. FAK in Cancer: from mechanisms to therapeutic strategies. Int J Mol Sci. 2022;23(3).
Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer. 2014;14(9):598–610.
pubmed: 25098269
pmcid: 4365862
doi: 10.1038/nrc3792
Martínez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021;21(10):669–80.
pubmed: 34272515
doi: 10.1038/s41568-021-00378-6
Chen W, Wen L, Bao Y, Tang Z, Zhao J, Zhang X, et al. Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2. Proc Natl Acad Sci USA. 2022;119(52):e2203894119.
pubmed: 36534812
pmcid: 9907126
doi: 10.1073/pnas.2203894119
Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, et al. Molecular pathways: Targeting IDO1 and other Tryptophan dioxygenases for Cancer Immunotherapy. Clin cancer Research: Official J Am Association Cancer Res. 2015;21(24):5427–33.
doi: 10.1158/1078-0432.CCR-15-0420
Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Nguyen B, et al. Tumor Cell IDO enhances Immune suppression and decreases Survival Independent of Tryptophan Metabolism in Glioblastoma. Clin cancer Research: Official J Am Association Cancer Res. 2021;27(23):6514–28.
doi: 10.1158/1078-0432.CCR-21-1392
Navarro MN, Gómez de Las Heras MM, Mittelbrunn M. Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing. Br J Pharmacol. 2022;179(9):1839–56.
pubmed: 33817782
doi: 10.1111/bph.15477
Seo SK, Kwon B. Immune regulation through tryptophan metabolism. Exp Mol Med. 2023;55(7):1371–9.
pubmed: 37394584
pmcid: 10394086
doi: 10.1038/s12276-023-01028-7
Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 2014;74(12):3317–31.
pubmed: 24755473
pmcid: 4885639
doi: 10.1158/0008-5472.CAN-14-0772-T
Roberti A, Fernández AF, Fraga MF. Nicotinamide N-methyltransferase: at the crossroads between cellular metabolism and epigenetic regulation. Mol Metabolism. 2021;45:101165.
doi: 10.1016/j.molmet.2021.101165
Liu D, Liang CH, Huang B, Zhuang X, Cui W, Yang L, et al. Tryptophan Metabolism acts as a New Anti-ferroptotic Pathway to Mediate Tumor Growth. Adv Sci (Weinheim Baden-Wurttemberg Germany). 2023;10(6):e2204006.
Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: beyond the migration of single cells. J Biol Chem. 2020;295(8):2495–505.
pubmed: 31937589
pmcid: 7039572
doi: 10.1074/jbc.REV119.007759
Läubli H, Borsig L. Altered cell adhesion and glycosylation promote Cancer Immune suppression and metastasis. Front Immunol. 2019;10:2120.
pubmed: 31552050
pmcid: 6743365
doi: 10.3389/fimmu.2019.02120
Basu A, Ramamoorthi G, Albert G, Gallen C, Beyer A, Snyder C, et al. Differentiation and regulation of T(H) cells: a Balancing Act for Cancer Immunotherapy. Front Immunol. 2021;12:669474.
pubmed: 34012451
pmcid: 8126720
doi: 10.3389/fimmu.2021.669474
Philip M, Schietinger A. CD8(+) T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022;22(4):209–23.
pubmed: 34253904
doi: 10.1038/s41577-021-00574-3
Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Reviews Clin Oncol. 2021;18(2):85–100.
doi: 10.1038/s41571-020-0426-7
Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell. 2023;41(3):450–65.
pubmed: 36917950
doi: 10.1016/j.ccell.2023.02.014
Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018;15(5):458–69.
pubmed: 29563615
pmcid: 6068176
doi: 10.1038/s41423-018-0004-4
Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184(21):5309–37.
pubmed: 34624224
pmcid: 8767569
doi: 10.1016/j.cell.2021.09.020
Zhang C, Cheng W, Ren X, Wang Z, Liu X, Li G, et al. Tumor Purity as an underlying key factor in Glioma. Clin cancer Research: Official J Am Association Cancer Res. 2017;23(20):6279–91.
doi: 10.1158/1078-0432.CCR-16-2598
Yue H, Li W, Chen R, Wang J, Lu X, Li J. Stromal POSTN induced by TGF-β1 facilitates the migration and invasion of ovarian cancer. Gynecol Oncol. 2021;160(2):530–8.
pubmed: 33317907
doi: 10.1016/j.ygyno.2020.11.026
Li C, Wang L. TFEB-dependent autophagy is involved in scavenger receptor OLR1/LOX-1-mediated tumor progression. Autophagy. 2022;18(2):462–4.
pubmed: 34936535
doi: 10.1080/15548627.2021.2012970
Ma B, Ueda H, Okamoto K, Bando M, Fujimoto S, Okada Y, et al. TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway. Cancer Sci. 2022;113(12):4244–57.
pubmed: 36073574
pmcid: 9746056
doi: 10.1111/cas.15567
Augoff K, Hryniewicz-Jankowska A, Tabola R, Stach K. MMP9: a tough target for targeted therapy for Cancer. Cancers. 2022;14(7).
Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17(8):807–21.
pubmed: 32612154
pmcid: 7395159
doi: 10.1038/s41423-020-0488-6
Huang Y, Jia A, Wang Y, Liu G. CD8(+) T cell exhaustion in anti-tumour immunity: the new insights for cancer immunotherapy. Immunology. 2023;168(1):30–48.
pubmed: 36190809
doi: 10.1111/imm.13588
Chu J, Gao F, Yan M, Zhao S, Yan Z, Shi B, et al. Natural killer cells: a promising immunotherapy for cancer. J Translational Med. 2022;20(1):240.
doi: 10.1186/s12967-022-03437-0
Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24.
pubmed: 31467405
doi: 10.1038/s41577-019-0210-z
Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021;21(5):298–312.
pubmed: 33750922
doi: 10.1038/s41568-021-00339-z
Boutilier AJ, Elsawa SF. Macrophage polarization States in the Tumor Microenvironment. Int J Mol Sci. 2021;22(13).
Liu S, Galat V, Galat Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol. 2021;14(1):7.
pubmed: 33407739
pmcid: 7788999
doi: 10.1186/s13045-020-01014-w
Bagchi S, Yuan R, Engleman EG. Immune Checkpoint inhibitors for the treatment of Cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49.
pubmed: 33197221
doi: 10.1146/annurev-pathol-042020-042741
He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020;30(8):660–9.
pubmed: 32467592
pmcid: 7395714
doi: 10.1038/s41422-020-0343-4
Pérez-Ruiz E, Melero I, Kopecka J, Sarmento-Ribeiro AB, García-Aranda M, De Las Rivas J. Cancer immunotherapy resistance based on immune checkpoints inhibitors: targets, biomarkers, and remedies. Drug Resist Updates: Reviews Commentaries Antimicrob Anticancer Chemother. 2020;53:100718.
doi: 10.1016/j.drup.2020.100718
Ladomersky E, Zhai L, Lauing KL, Bell A, Xu J, Kocherginsky M, et al. Advanced Age increases Immunosuppression in the brain and decreases immunotherapeutic efficacy in subjects with Glioblastoma. Clin cancer Research: Official J Am Association Cancer Res. 2020;26(19):5232–45.
doi: 10.1158/1078-0432.CCR-19-3874
Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-derived suppressor cells as a therapeutic target for Cancer. Cells. 2020;9(3).
Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Reviews Clin Oncol. 2021;18(12):792–804.
doi: 10.1038/s41571-021-00546-5
Xuan W, Lesniak MS, James CD, Heimberger AB, Chen P. Context-dependent Glioblastoma-Macrophage/Microglia symbiosis and Associated mechanisms. Trends Immunol. 2021;42(4):280–92.
pubmed: 33663953
pmcid: 8005482
doi: 10.1016/j.it.2021.02.004
Simonds EF, Lu ED, Badillo O, Karimi S, Liu EV, Tamaki W et al. Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma. J Immunother Cancer. 2021;9(6).
Khan F, Pang L, Dunterman M, Lesniak MS, Heimberger AB, Chen P. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. J Clin Investig. 2023;133(1).
Lu L, Chen G, Yang J, Ma Z, Yang Y, Hu Y, et al. Bone marrow mesenchymal stem cells suppress growth and promote the apoptosis of glioma U251 cells through downregulation of the PI3K/AKT signaling pathway. Volume 112. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie; 2019. p. 108625.
Akimoto K, Kimura K, Nagano M, Takano S, To’a Salazar G, Yamashita T, et al. Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev. 2013;22(9):1370–86.
pubmed: 23231075
doi: 10.1089/scd.2012.0486
Oishi T, Koizumi S, Kurozumi K. Mesenchymal stem cells as therapeutic vehicles for glioma. Cancer Gene Ther. 2024;31(9):1306–14.
Corona A, Blobe GC. The role of the extracellular matrix protein TGFBI in cancer. Cell Signal. 2021;84:110028.
pubmed: 33940163
doi: 10.1016/j.cellsig.2021.110028
Puthdee N, Sriswasdi S, Pisitkun T, Ratanasirintrawoot S, Israsena N, Tangkijvanich P. The LIN28B/TGF-β/TGFBI feedback loop promotes cell migration and tumour initiation potential in cholangiocarcinoma. Cancer Gene Ther. 2022;29(5):445–55.
pubmed: 34548635
doi: 10.1038/s41417-021-00387-5
Kano J, Wang H, Zhang H, Noguchi M. Roles of DKK3 in cellular adhesion, motility, and invasion through extracellular interaction with TGFBI. FEBS J. 2022;289(20):6385–99.
pubmed: 35574828
doi: 10.1111/febs.16529
Fico F, Santamaria-Martínez A. TGFBI modulates tumour hypoxia and promotes breast cancer metastasis. Mol Oncol. 2020;14(12):3198–210.
pubmed: 33080107
pmcid: 7718944
doi: 10.1002/1878-0261.12828
Han B, Cai H, Chen Y, Hu B, Luo H, Wu Y, et al. The role of TGFBI (βig-H3) in gastrointestinal tract tumorigenesis. Mol Cancer. 2015;14:64.
pubmed: 25889002
pmcid: 4435624
doi: 10.1186/s12943-015-0335-z
Ahmed AA, Mills AD, Ibrahim AE, Temple J, Blenkiron C, Vias M, et al. The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel. Cancer Cell. 2007;12(6):514–27.
pubmed: 18068629
pmcid: 2148463
doi: 10.1016/j.ccr.2007.11.014