S100A proteins show a spatial distribution of inflammation associated with the glioblastoma microenvironment architecture.

in Theranostics by Blanca Cómitre-Mariano, Berta Segura-Collar, Gabriel Vellila-Alonso, Rubén Contreras, Aurelio Henandez-Lain, Manuel Valiente, Juan M Sepulveda, Stephen Garrett Marcus, Guillermo García-Posadas, Luis Jiménez-Roldán, Ángel Perez-Nuñez, Ricardo Gargini

TLDR

  • The study found that S100A proteins play a crucial role in the inflammatory processes involved in GBM IDH wt, and that targeting these proteins could be a promising therapeutic approach.
  • The study analyzed the expression of S100A proteins in GBM IDH wt and identified their distinct functions in the microenvironment, and found that the RAGE inhibitor, Azeliragon, can reverse the alterations caused by S100A proteins.

Abstract

Glioblastoma IDH wild type (GBM IDH wt) has a poor prognosis and a strongly associated with inflammatory processes. Inflammatory molecules generate positive feedback with tumor cells fueling tumor growth as well as recruitment of immune cells that promote aggressiveness. Although the role of many inflammatory molecules is well known, there are many macromolecules, such as the S100A proteins, whose role is only now beginning to be established.Using RNA-seq, bioinformatics tools and a cohort of glioma patients to validate the results, we have analysed the inflammatory processes involved in glioma. Transcriptional profiles were also used to define biological processes of relevance to specific S100A proteins. Finally, we characterized the relevant immune populations with an IHC analysis and transcriptional profiling.We have noted an increased expression of S100A in GBM IDH wt compared to gliomas IDH mutants. This allowed us to analyse the involvement of different members of the family, such as S100A9, A11 and A13 as possible regulators of inflammatory processes in the GBM-IDH wt microenvironment. Thus, we observed that S100A9 is located in hypoxic areas linked to the function of neutrophils, S100A11 is found in vascular areas associated with the function of perivascular pericytes and macrophages, and finally, S100A13 which is related to the dysfunction of microglia.Our findings define different functions for S100A9, A11 and A13 proteins that are associated with the architecture of the glioblastoma microenvironment and define its progression. Moreover, these alterations can be reversed by the RAGE inhibitor, Azeliragon which is in a phase I/II clinical trial NCT05635734.

Overview

  • The study aimed to investigate the role of S100A proteins in glioblastoma IDH wild type (GBM IDH wt), which has a poor prognosis and is associated with inflammatory processes.
  • The researchers used RNA-seq, bioinformatics tools, and a cohort of glioma patients to analyze the inflammatory processes involved in glioma and the biological processes of specific S100A proteins.
  • The study characterized the relevant immune populations using IHC analysis and transcriptional profiling, and identified the involvement of different S100A family members as regulators of inflammatory processes in the GBM-IDH wt microenvironment.

Comparative Analysis & Findings

  • The researchers noted an increased expression of S100A proteins in GBM IDH wt compared to gliomas IDH mutants, and analyzed the involvement of different S100A family members in regulating inflammatory processes.
  • S100A9 was found to be located in hypoxic areas linked to neutrophil function, S100A11 in vascular areas associated with perivascular pericyte and macrophage function, and S100A13 related to microglial dysfunction.
  • The study found that S100A9, A11, and A13 proteins have distinct functions associated with the architecture of the glioblastoma microenvironment and its progression, and that these alterations can be reversed by the RAGE inhibitor, Azeliragon.

Implications and Future Directions

  • The study's findings define the different functions of S100A9, A11, and A13 proteins in the glioblastoma microenvironment, and highlight their potential as therapeutic targets for GBM IDH wt.
  • The study suggests that targeting S100A proteins could be a promising approach for treating GBM IDH wt, and future research could explore the role of these proteins in other types of cancer.
  • Future studies could also investigate the potential of Azeliragon as a therapeutic agent for GBM IDH wt, as well as the mechanism by which it reverses the alterations caused by S100A proteins.
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