Skip to main content

Advertisement

SpringerLink
Log in

Cell signaling activation and extracellular matrix remodeling underpin glioma tumor microenvironment heterogeneity and organization

  • Original Article
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Tumor cells thrive by adapting to the signals in their microenvironment. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells.

Methods

Multiplex immunohistochemistry, spatial analysis and histological dyes were used to identify and measure immune cell infiltration, cell signal activation and extracellular matrix deposition in low-grade, high-grade astrocytoma and glioblastoma.

Results

We show that lower grade astrocytoma tissue is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade astrocytoma exhibits abundant immune cell infiltration, activation, and extensive tissue remodeling. Spatial analysis shows that most T-cells are restricted to perivascular regions, but bone marrow-derived macrophages penetrate deep into neoplastic cell-rich regions. The tumor microenvironment is characterized by heterogeneous PI3K, MAPK and CREB signaling, with specific signaling profiles correlating with distinct pathological hallmarks, including angiogenesis, tumor cell density and regions where neoplastic cells border the extracellular matrix. Our results also show that tissue remodeling is important in regulating the architecture of the tumor microenvironment during tumor progression.

Conclusion

The tumor microenvironment in malignant astrocytoma, exhibits changes in cell composition, cell signaling activation and extracellular matrix deposition during disease development and that targeting the extracellular matrix, as well as cell signaling activation will be critical to designing personalized therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Not applicable.

References

  1. C. Wild, E. Weiderpass, B.W. Stewart, World cancer Report: cancer Research for cancer Prevention (IARC Press, 2020)

  2. D.N. Louis, A. Perry, P. Wesseling, D.J. Brat, I.A. Cree, D. Figarella-Branger et al., The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23, 1231–1251 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. D.N. Louis, A. Perry, G. Reifenberger, A. von Deimling, D. Figarella-Branger, W.K. Cavenee et al., The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131, 803–820 (2016)

    Article  PubMed  Google Scholar 

  4. R. Stupp, W.P. Mason, M.J. van den Bent, M. Weller, B. Fisher, M.J.B. Taphoorn et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl. J. Med 352, 987–996 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. H.S. Phillips, S. Kharbanda, R. Chen, W.F. Forrest, R.H. Soriano, T.D. Wu et al., Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008)

    Article  Google Scholar 

  7. C.W. Brennan, R.G.W. Verhaak, A. McKenna, B. Campos, H. Noushmehr, S.R. Salama et al., The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. S. Darmanis, S.A. Sloan, D. Croote, M. Mignardi, S. Chernikova, P. Samghababi et al., Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell. Rep 21, 1399–1410 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. C.P. Couturier, S. Ayyadhury, P.U. Le, J. Nadaf, J. Monlong, G. Riva et al., Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat. Commun 11, 3406 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. M. Castellan, A. Guarnieri, A. Fujimura, F. Zanconato, G. Battilana, T. Panciera et al., Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma. Nat. Cancer 2, 174–188 (2021)

    Article  CAS  PubMed  Google Scholar 

  11. L.M. Richards, O.K.N. Whitley, G. MacLeod, F.M.G. Cavalli, F.J. Coutinho, J.E. Jaramillo et al., Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity. Nat. Cancer 2, 157–173 (2021)

    Article  CAS  PubMed  Google Scholar 

  12. M. Rahman, J. Kresak, C. Yang, J. Huang, W. Hiser, P. Kubilis et al., Analysis of immunobiologic markers in primary and recurrent glioblastoma. J. Neurooncol 137, 249–257 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. D. Yan, J. Kowal, L. Akkari, A.J. Schuhmacher, J.T. Huse, B.L. West et al., Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene 36, 6049–6058 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. B.M. Andersen, C. Faust Akl, M.A. Wheeler, E.A. Chiocca, D.A. Reardon, F.J. Quintana, Glial and myeloid heterogeneity in the brain tumour microenvironment. Nat. Rev. Cancer (2021). https://doi.org/10.1038/s41568-021-00397-3

    Article  PubMed  PubMed Central  Google Scholar 

  15. M.G. García-Mendoza, D.R. Inman, S.M. Ponik, J.J. Jeffery, D.S. Sheerar, R.R. Van Doorn et al., Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironment. Breast Cancer Res 18, 49 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  16. C.E. Barcus, P.Y. Hwang, V. Morikis, A. Brenot, P. Pence, M. Clarke et al. Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis. J. Cell. Sci. 134 (2021). https://doi.org/10.1242/jcs.258431

  17. J.T. Rutka, C.A. Myatt, J.R. Giblin, R.L. Davis, M.L. Rosenblum, Distribution of extracellular matrix proteins in primary human brain tumours: an immunohistochemical analysis. Can. J. Neurol. Sci 14, 25–30 (1987)

    Article  CAS  PubMed  Google Scholar 

  18. H. Wang, Z. Liu, A. Li, J. Wang, J. Liu, B. Liu et al., COL4A1 as a novel oncogene associated with the clinical characteristics of malignancy predicts poor prognosis in glioma. Exp. Ther. Med 22, 1224 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. L. MacCarthy-Morrogh, P. Martin. The hallmarks of cancer are also the hallmarks of wound healing. Sci. Signal. 13 (2020). https://doi.org/10.1126/scisignal.aay8690

  20. P.M. Burkholder, Atlas of Human Glomerular Pathology: Correlative Light, Immunofluorescence, and Ultrastructural Histology (HarperCollins Publishers, 1974)

  21. Hunter. Matplotlib: A 2D Graphics Environment. Comput. Sci. Eng. 9(03), 90–95 (2007)

  22. J. Yuan, H.M. Levitin, V. Frattini, E.C. Bush, D.M. Boyett, J. Samanamud et al., Single-cell transcriptome analysis of lineage diversity in high-grade glioma. Genome Med 10, 57 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  23. A. Butler, P. Hoffman, P. Smibert, E. Papalexi, R. Satija, Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol 36, 411–420 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. P.M. Daniel, G. Filiz, D.V. Brown, M. Christie, P.M. Waring, Y. Zhang et al., PI3K activation in neural stem cells drives tumorigenesis which can be ameliorated by targeting the cAMP response element binding protein. Neuro Oncol 20, 1344–1355 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. D.F. Quail, J.A. Joyce, The microenvironmental landscape of brain tumors. Cancer Cell 31, 326–341 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. J. Kowal, M. Kornete, J.A. Joyce, Re-education of macrophages as a therapeutic strategy in cancer. Immunotherapy 11, 677–689 (2019)

    Article  CAS  PubMed  Google Scholar 

  27. Cancer Genome Atlas Research Network, D.J. Brat, R.G.W. Verhaak, K.D. Aldape, W.K.A. Yung, S.R. Salama et al., Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl. J. Med 372, 2481–2498 (2015)

    Article  Google Scholar 

  28. J.A. Miller, S.-L. Ding, S.M. Sunkin, K.A. Smith, L. Ng, A. Szafer et al., Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. A.M. Newman, C.L. Liu, M.R. Green, A.J. Gentles, W. Feng, Y. Xu et al., Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. A.J. Shaywitz, M.E. Greenberg, CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem 68, 821–861 (1999)

    Article  CAS  PubMed  Google Scholar 

  31. P.M. Daniel, G. Filiz, M.J. Tymms, R.G. Ramsay, A.H. Kaye, S.S. Stylli et al., Intratumor MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with CREB signaling and distinct target gene signatures. Exp. Mol. Pathol 105, 23–31 (2018)

    Article  CAS  PubMed  Google Scholar 

  32. S. Baumann, B. Kyewski, S.C. Bleckmann, E. Greiner, D. Rudolph, W. Schmid et al., CREB function is required for normal thymic cellularity and post-irradiation recovery. Eur. J. Immunol 34, 1961–1971 (2004)

    Article  CAS  PubMed  Google Scholar 

  33. K. Barton, N. Muthusamy, M. Chanyangam, C. Fischer, C. Clendenin, J.M. Leiden, Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature 379, 81–85 (1996)

    Article  CAS  PubMed  Google Scholar 

  34. B. Mastelic-Gavillet, B. Navarro Rodrigo, L. Décombaz, H. Wang, G. Ercolano, R. Ahmed et al., Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8 + T cells. J. Immunother Cancer 7, 257 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  35. F. Zhang, M. Rincon, R.A. Flavell, T.M. Aune, Defective th function induced by a dominant-negative cAMP response element binding protein mutation is reversed by Bcl-2. J. Immunol 165, 1762–1770 (2000)

    Article  CAS  PubMed  Google Scholar 

  36. K. Ohl, A. Schippers, K. Tenbrock, CD11c-Specific deletion reveals CREB as a critical regulator of DC function during the germinal center response. J. Immunol. Res 2018, 8947230 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  37. B. Luan, Y.-S. Yoon, J. Le Lay, K.H. Kaestner, S. Hedrick, M. Montminy, CREB pathway links PGE2 signaling with macrophage polarization. Proc. Natl. Acad. Sci. U S A 112, 15642–15647 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. L. Perria, U. Sacchi, [Incidence of age factor and tumoral stroma on the course of glioblastoma]. Sist Nerv 2, 176–186 (1950)

    CAS  PubMed  Google Scholar 

  39. U. Novak, A.H. Kaye, Extracellular matrix and the brain: components and function. J. Clin. Neurosci 7, 280–290 (2000)

    Article  CAS  PubMed  Google Scholar 

  40. D.V. Brown, G. Filiz, P.M. Daniel, F. Hollande, S. Dworkin, S. Amiridis et al., Expression of CD133 and CD44 in glioblastoma stem cells correlates with cell proliferation, phenotype stability and intra-tumor heterogeneity. PLoS ONE 12, e0172791 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  41. M. Ceccarelli, F.P. Barthel, T.M. Malta, T.S. Sabedot, S.R. Salama, B.A. Murray et al., Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. B. Weenink, K. Draaisma, H.Z. Ooi, J.M. Kros, P.A.E. Sillevis Smitt, R. Debets et al., Low-grade glioma harbors few CD8 T cells, which is accompanied by decreased expression of chemo-attractants, not immunogenic antigens. Sci. Rep 9, 14643 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  43. F. Klemm, R.R. Maas, R.L. Bowman, M. Kornete, K. Soukup, S. Nassiri et al., Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181, 1643-1660.e17 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. A.R. Pombo Antunes, I. Scheyltjens, F. Lodi, J. Messiaen, A. Antoranz, J. Duerinck et al., Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat. Neurosci 24, 595–610 (2021)

    Article  CAS  PubMed  Google Scholar 

  45. M.H. Robinson, J. Vasquez, A. Kaushal, T.J. MacDonald, J.E. Velázquez Vega, M. Schniederjan et al. Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma. J. Immunother Cancer. 8 (2020). https://doi.org/10.1136/jitc-2020-001066

  46. K. Yan, Y. Lu, Z. Yan, Y. Wang, 9-Gene signature correlated with CD8 + T cell infiltration activated by IFN-γ: a biomarker of immune checkpoint therapy response in melanoma. Front. Immunol 12, 622563 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. F. Basit, T. van Oorschot, J. van Buggenum, R.J.E. Derks, S. Kostidis, M. Giera et al., Metabolomic and lipidomic signatures associated with activation of human cDC1 (BDCA3+ /CD141+) dendritic cells. Immunology (2021). https://doi.org/10.1111/imm.13409

    Article  PubMed  Google Scholar 

  48. Y. Sun, A.J. Sedgwick, Y. Palarasah, S. Mangiola, A.D. Barrow, A transcriptional signature of PDGF-DD activated natural killer cells predicts more favorable prognosis in low-grade glioma. Front. Immunol 12, 668391 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Y.R. Na, J.W. Kwon, D.Y. Kim, H. Chung, J. Song, D. Jung et al., Protein kinase A catalytic subunit is a molecular switch that promotes the pro-tumoral function of macrophages. Cell. Rep 31, 107643 (2020)

    Article  CAS  PubMed  Google Scholar 

  50. X. Su, Y. Xu, G.C. Fox, J. Xiang, K.A. Kwakwa, J.L. Davis et al. Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment. J. Clin. Invest. 131 (2021). https://doi.org/10.1172/JCI145296

  51. J.R.D. Pearson, T. Regad, Targeting cellular pathways in glioblastoma multiforme. Signal. Transduct. Target. Ther 2, 17040 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  52. P.P. Provenzano, K.W. Eliceiri, J.M. Campbell, D.R. Inman, J.G. White, P.J. Keely, Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med (2006). https://doi.org/10.1186/1741-7015-4-38

    Article  PubMed  PubMed Central  Google Scholar 

  53. A. Rambur, C. Lours-Calet, C. Beaudoin, J. Buñay, M. Vialat, V. Mirouse et al., Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila. Nat. Commun 11, 2300 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Y.A. Yabo, S.P. Niclou, A. Golebiewska, Cancer cell heterogeneity and plasticity: a paradigm shift in glioblastoma. Neuro Oncol 24, 669–682 (2022)

    Article  CAS  PubMed  Google Scholar 

  55. Q. Xie, S. Mittal, M.E. Berens, Targeting adaptive glioblastoma: an overview of proliferation and invasion. Neuro Oncol 16, 1575–1584 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. H. Hatzikirou, D. Basanta, M. Simon, K. Schaller, A. Deutsch, “Go or grow”: the key to the emergence of invasion in tumour progression? Math. Med. Biol 29, 49–65 (2012)

    Article  CAS  PubMed  Google Scholar 

  57. Q.T. Ostrom, H. Gittleman, J. Xu, C. Kromer, Y. Wolinsky, C. Kruchko et al., CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro Oncol 18, v1–v75 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  58. A. Garate-Carrillo, J. Gonzalez, G. Ceballos, I. Ramirez-Sanchez, F. Villarreal, Sex related differences in the pathogenesis of organ fibrosis. Transl Res 222, 41–55 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. G. Escobar, B. Gentner, L. Naldini, R. Mazzieri, Engineered tumor-infiltrating macrophages as gene delivery vehicles for interferon-α activates immunity and inhibits breast cancer progression. Oncoimmunology 3, e28696 (2014)

  60. L. Griffiths, K. Binley, S. Iqball, O. Kan, P. Maxwell, P. Ratcliffe et al., The macrophage - a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 7, 255–262 (2000)

    Article  CAS  PubMed  Google Scholar 

  61. A.Y. Tsidulko, C. Bezier, G. de La Bourdonnaye, A.V. Suhovskih, T.M. Pankova, G.M. Kazanskaya et al., Conventional anti-glioblastoma chemotherapy affects proteoglycan composition of brain extracellular matrix in rat experimental model in vivo. Front. Pharmacol 9, 1104 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. A. Zomer, D. Croci, J. Kowal, L. van Gurp, J.A. Joyce, Multimodal imaging of the dynamic brain tumor microenvironment during glioblastoma progression and in response to treatment. iScience 25, 104570 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. A. Comba, S.M. Faisal, P.J. Dunn, A.E. Argento, T.C. Hollon, W.N. Al-Holou et al., Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression. Nat. Commun 13, 3606 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Metta Jana, Rejhan Idrizi and Ian Birchall for advice on tissue preparation, histology and staining. Marlene Hao and Lincon Stamp for reagents and scientific discussion.

Funding

This work was supported by the CASS Foundation Australia (grants 6236 and 7941) for T.M., Department of Surgery (RMH) and School of Biomedical Sciences translational research grant for T.M. and F.M.

Author information

Author notes

  1. Fabienne MacKay

    Present address: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

  2. Marija Dinevska and Samuel S. Widodo contributed equally.

Authors and Affiliations

  1. Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia

    Marija Dinevska, Samuel S. Widodo, Stanley S. Stylli & Theo Mantamadiotis

  2. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia

    Liam Furst, Lucero Cuzcano, Yitong Fang, Fabienne MacKay & Theo Mantamadiotis

  3. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia

    Stefano Mangiola

  4. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Paul J. Neeson, Phillip K. Darcy & Robert G. Ramsay

  5. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia

    Paul J. Neeson, Phillip K. Darcy & Robert G. Ramsay

  6. Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia

    Ryan Hutchinson

  7. Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, VIC, Australia

    Michael Christie

  8. Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia

    Stanley S. Stylli

  9. Centre for Stem Cell Systems, The University of Melbourne, Parkville, VIC, Australia

    Theo Mantamadiotis

Authors
  1. Marija Dinevska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel S. Widodo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liam Furst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucero Cuzcano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yitong Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefano Mangiola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul J. Neeson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Phillip K. Darcy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert G. Ramsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ryan Hutchinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fabienne MacKay
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Christie
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stanley S. Stylli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Theo Mantamadiotis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.D. and S.S.W. performed most of the experimental work, data analysis and wrote parts of the manuscript. L.F. and L.C. performed immunohistochemical analysis experiments. Y.F. and S.M. performed the computational analysis experiments. P.N., P.D. and R.R. provided expertise on multiplex immunohistochemical analysis optimization experiments. F.M. provided expertise on tumor immunology and antibody panel selection. M.C. performed the histopathological analysis and IDH immunohistochemistry. S.S. provided expertise for glioma tissue selection and co-conceived the project. T.M. is the principal investigator who conceived the project, supervised research, and wrote and edited the manuscript.

Corresponding author

Correspondence to Theo Mantamadiotis.

Ethics declarations

Ethical approval and consent to participate

Not applicable.

Human ethics

Human ethics approval for tissue use was covered by project application 1853511 and was approved by the Medicine and Dentistry Human Ethics Sub-Committee, The University of Melbourne. For TMA specimens, all tissue was collected with patient and/or family consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1.53 MB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dinevska, M., Widodo, S.S., Furst, L. et al. Cell signaling activation and extracellular matrix remodeling underpin glioma tumor microenvironment heterogeneity and organization. Cell Oncol. 46, 589–602 (2023). https://doi.org/10.1007/s13402-022-00763-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-022-00763-9

Keywords

Search

Navigation