Microglia-derived olfactomedin-like 3 promotes pro-tumorigenic microglial function and malignant features of glioma cells

Ryan G. Toedebusch, Christopher A. Lucchesi, Eshetu T. Debebe, Luke A. Wittenburg, Xinbin Chen, Christine M. Toedebusch

Research output: Contribution to journalArticlepeer-review

Abstract

Under the influence of transforming growth factor-beta (TGFβ), glioma-associated mi-croglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (Olfml3), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in microglia, the role of microglia-derived OLFML3 in glioma progression is unknown. Here, we tested the hypotheses that microglial Olfml3 is integral to the pro-tumorigenic glioma-associated microglia phenotype and promotes glioma cell malignancy. Using an Olfml3 knockout microglial cell line (N9), we demonstrated that Olfml3 is a direct target gene of all TGFβ iso-forms in murine microglia. Moreover, loss of Olfml3 attenuated TGFβ-induced restraint on microglial immune function and production of cytokines that are critical in promoting glioma cell malignancy. Importantly, microglia-derived OLFML3 directly contributes to glioma cell malignancy through increased migration and invasion. While exposure to conditioned medium (CM) from isogenic control microglia pre-treated with TGFβ increased mouse glioma cell (GL261) migration and invasion, this effect was abolished with exposure to CM from TGFβ-treated Olfml3-/- microglia. Taken together, our data suggest that Olfml3 may serve as a gatekeeper for TGFβ-induced microglial gene expression, thereby promoting the pro-tumorigenic microglia phenotype and glioma cell malignancy.

Original languageEnglish (US)
Article number13052
JournalInternational journal of molecular sciences
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2021

Keywords

  • Glioblastoma
  • Microglia
  • Olfactomedin-like 3
  • TGFβ

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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