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Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma

Kiyotaka Yokogami1, Takashi Watanabe2, Shinji Yamashita2

  • 1Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan. akatoyik@med.miyazaki-u.ac.jp.

Journal of Neuro-Oncology
|March 6, 2024
PubMed
Abstract

Insights

Targeting the GREM2-BMPR1A pathway in meningiomas offers a new therapeutic strategy. This approach modulates tryptophan metabolism, reduces energy production, and induces senescence in malignant brain tumors.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Meningiomas are common brain tumors, often benign, but malignant subtypes recur with poor prognosis.
  • Current treatments for recurrent meningiomas are limited, highlighting the need for novel therapeutic targets.
  • Meningioma metabolism remains poorly understood, hindering the development of effective treatments.

Purpose of the Study:

  • To identify a novel therapeutic target for recurrent and malignant meningiomas.
  • To investigate the role of bone morphogenetic protein (BMP) signaling and Gremlin2 (GREM2) in meningioma progression.
  • To elucidate the metabolic alterations in malignant meningiomas.

Main Methods:

  • Examined the effects of a BMP signal inhibitor (K02288) and GREM2 on meningioma growth and senescence.
  • Assessed proliferation by inhibiting BMP signaling and analyzed GREM2 overexpression.
  • Correlated GREM2 mRNA expression with proliferation markers in clinical samples and analyzed RNA-seq data.
  • Investigated metabolic and senescence marker changes following BMP signal suppression.

Main Results:

  • Inhibiting BMP receptor (BMPR1A) and overexpressing GREM2 shifted tryptophan metabolism towards serotonin, reducing NAD+/NADH and ATP production.
  • Decreased expression of genes involved in oxidative phosphorylation was observed in malignant meningiomas.
  • Malignant meningiomas exhibited cellular senescence, reduced proliferation, and psammoma body formation.
  • Analysis of clinical and public RNA-seq data confirmed that increased GREM2 expression correlates with reduced oxidative phosphorylation gene expression.

Conclusions:

  • The GREM2-BMPR1A-tryptophan metabolic pathway represents a potential therapeutic target for meningiomas.
  • Modulating this pathway may offer a new strategy for treating aggressive meningioma subtypes.
  • Understanding meningioma metabolism is crucial for developing targeted therapies.
Keywords:
BMPGREM2Induced calcificationMalignant meningiomaSenescence

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