Prognosis and Clinical features Analysis of EMT-related Signature and Tumor Immune Microenvironment in Glioma

EMT-related Subtypes of glioblastoma

  • Zheng Xiao Department of Neurosurgery, Zhujiang Hospital, Southern Medical University
  • Xiaoyan Liu
  • Yixiang Mo
  • Weibo Chen
  • Shizhong Zhang
  • Yingwei Yu
  • Huiwen Weng
DOI: https://doi.org/10.5937/jomb0-39234
Keywords: Glioma, epithelial mesenchymal transition, tumor microenvironment, immunotherapy, risk score

Abstract


Background: As the most common primary malignant intracranial tumor, glioblastoma has a poor prognosis with limited treatment options. It has a high propensity for recurrence, invasion, and poor immune prognosis due to thecomplex tumor microenvironment.

Methods: Six groups of samples from four datasets were included in this study. We used consensusClusterPlus to establish two subgroups by the EMT-related gene. The difference in clinicopathological features, genomic characteristics, Immune infiltration, treatment response and prognoses were evaluated by multiple algorithms. By using LASSO regression, multi-factor Cox analysis, stepAIC method, A prognostic risk model was constructed based on the final screened genes.

Results: The consensusClusterPlus analyses revealed two subtypes of glioblastoma (C1 and C2), which were characterized by different EMT-related gene expression patterns. C2 subtype with the worse prognosis had the more malignant clinical and pathology manifestations, higher Immune infiltration and tumor-associated molecular pathways scores, and poorer response to treatment. Additionally, our EMT-related genes risk prediction model can provide valuable support for clinical evaluations of glioma.

Conclusions: The assessment system and prediction model displayed good performance in independent prognostic risk assessment and individual patient treatment response prediction. This can help with clinical treatment decisions and the development of effective treatments.

References

1. van Solinge TS, Nieland L, Chiocca EA, Broekman M. Advances in local therapy for glioblastoma - taking the fight to the tumour. Nat Rev Neurol 2022; 18(4): 221-36.
2. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ 2021; 374: n1560.
3. Andersen BM, Faust AC, Wheeler MA, Chiocca EA, Reardon DA, Quintana FJ. Glial and myeloid heterogeneity in the brain tumour microenvironment. Nat Rev Cancer 2021; 21(12): 786-802.
4. Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. Author Correction: EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 2022; 19(5): 357-8.
5. Gittleman H, Lim D, Kattan MW, Chakravarti A, Gilbert MR, Lassman AB, et al. An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825. Neuro Oncol 2017; 19(5): 669-77.
6. Lah TT, Novak M, Breznik B. Brain malignancies: Glioblastoma and brain metastases. Semin Cancer Biol 2020; 60: 262-73.
7. Mahabir R, Tanino M, Elmansuri A, Wang L, Kimura T, Itoh T, et al. Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. Neuro Oncol 2014; 16(5): 671-85.
8. Schmitt MJ, Company C, Dramaretska Y, Barozzi I, Gohrig A, Kertalli S, et al. Phenotypic Mapping of Pathologic Cross-Talk between Glioblastoma and Innate Immune Cells by Synthetic Genetic Tracing. Cancer Discov 2021; 11(3): 754-77.
9. Chen T, Zhang F, Liu J, Huang Z, Zheng Y, Deng S, et al. Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells. Oncogene 2021; 40(32): 5081-94.
10. Shah MA, Hofstetter WL, Kennedy EB. Immunotherapy in Patients With Locally Advanced Esophageal Carcinoma: ASCO Treatment of Locally Advanced Esophageal Carcinoma Guideline Rapid Recommendation Update. J Clin Oncol 2021; 39(28): 3182-4.
11. Powles T, Albiges L, Bex A, Grunwald V, Porta C, Procopio G, et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol 2021; 32(12): 1511-9.
12. Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, et al. A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma. Neuro Oncol 2019; 21(3): 348-59.
13. Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 2017; 18(10): 1373-85.
14. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 2012; 28(6): 882-3.
15. Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 2010; 26(12): 1572-3.
16. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43(7): e47.
17. Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 2016; 17(1): 218.
18. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res 2017; 77(21): e108-10.
19. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013; 4: 2612.
20. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade. Cell Rep 2017; 18(1): 248-62.
21. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015; 12(5): 453-7.
22. Zhang X, Klamer B, Li J, Fernandez S, Li L. A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer. Bmc Med Genomics 2020; 13(Suppl 5): 45.
23. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 2007; 39(2): 237-42.
24. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128(4): 683-92.
25. Malta TM, Sokolov A, Gentles AJ, Burzykowski T, Poisson L, Weinstein JN, et al. Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation. Cell 2018; 173(2): 338-54.
26. Fu J, Li K, Zhang W, Wan C, Zhang J, Jiang P, et al. Large-scale public data reuse to model immunotherapy response and resistance. Genome Med 2020; 12(1): 21.
27. Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 2018; 24(10): 1550-8.
28. Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell 2017; 171(4): 934-49.
29. Roh W, Chen PL, Reuben A, Spencer CN, Prieto PA, Miller JP, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med 2017; 9(379): eaah3560.
30. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554(7693): 544-8.
31. Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. Bmc Bioinformatics 2013; 14: 7.
32. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell 2016; 164(3): 550-63.
33. Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin 2020; 70(4): 299-312.
34. Grabowski MM, Sankey EW, Ryan KJ, Chongsathidkiet P, Lorrey SJ, Wilkinson DS, et al. Immune suppression in gliomas. J Neurooncol 2021; 151(1): 3-12.
35. Guan T, Dominguez CX, Amezquita RA, Laidlaw BJ, Cheng J, Henao-Mejia J, et al. ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8(+) T cell fates. J Exp Med 2018; 215(4): 1153-68.
36. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 2019; 20(2): 69-84.
Published
2022/08/31
Issue
Vol. 42 No. 1 (2023): Journal of Medical Biochemistry
Section
Original paper

Copyright (c) 2022 Zheng Xiao, Xiaoyan Liu, Yixiang Mo, Weibo Chen, Shizhong Zhang, Yingwei Yu, Huiwen Weng

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.

Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.