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Review
. 2024 Oct;40(10):3209-3221.
doi: 10.1007/s00381-024-06463-z. Epub 2024 May 25.

MOST wanted: navigating the MAPK-OIS-SASP-tumor microenvironment axis in primary pediatric low-grade glioma and preclinical models

Romain Sigaud  1   2   3 , Tilman Brummer  4   5   6 , Daniela Kocher  7   8   9   10 , Till Milde  7   8   9   11 , Florian Selt  12   13   14   15
Affiliations
Review

MOST wanted: navigating the MAPK-OIS-SASP-tumor microenvironment axis in primary pediatric low-grade glioma and preclinical models

Romain Sigaud et al. Childs Nerv Syst. 2024 Oct.

Abstract

Understanding the molecular and cellular mechanisms driving pediatric low-grade glioma (pLGG)-the most prevalent brain tumor in children-is essential for the identification and evaluation of novel effective treatments. This review explores the intricate relationship between the mitogen-activated protein kinase (MAPK) pathway, oncogene-induced senescence (OIS), the senescence-associated secretory phenotype (SASP), and the tumor microenvironment (TME), integrating these elements into a unified framework termed the MAPK/OIS/SASP/TME (MOST) axis. This integrated approach seeks to deepen our understanding of pLGG and improve therapeutic interventions by examining the MOST axis' critical influence on tumor biology and response to treatment. In this review, we assess the axis' capacity to integrate various biological processes, highlighting new targets for pLGG treatment, and the need for characterized in vitro and in vivo preclinical models recapitulating pLGG's complexity to test targets. The review underscores the need for a comprehensive strategy in pLGG research, positioning the MOST axis as a pivotal approach in understanding pLGG. This comprehensive framework will open promising avenues for patient care and guide future research towards inventive treatment options.

Keywords: MAPK pathway; Microenvironment; Oncogene-induced senescence; Pediatric low-grade glioma; Senescence-associated secretory phenotype.

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Conflict of interest statement

T.M. was supported by research grants from Biomed Valley Discoveries, Inc., and Day One Biopharmaceuticals.

Figures

Fig. 1
Fig. 1
MAPK pathway in pediatric low-grade gliomas. RTK, receptor tyrosine kinase. Percentages from [7]
Fig. 2
Fig. 2
Molecular and cellular features of oncogene-induced senescence. SA-b-GAL, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; SASP, senescence-associated secretory phenotype
Fig. 3
Fig. 3
Tumor microenvironment composition and main features in pLGG. MSS, MAPKi sensitivity score; BBB, blood–brain barrier
Fig. 4
Fig. 4
Integrated view of the MAPK/OIS/SASP/TME axis
Fig. 5
Fig. 5
Overview of the MOST modeling strategies. NSC, neural stem cells; GEMM, genetically engineered mouse model; hiPSC, human-induced pluripotent stem cells
See this image and copyright information in PMC

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