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The Novel Protein, Olfactomedin‐like 3, Alters Microglia Biology and May Contribute to Glioma Progression
Author(s) -
Toedebusch Ryan,
Wittenburg Luke,
Debebe Eshetu,
Lucchesi Chris,
Toedebusch Christine
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04385
Subject(s) - microglia , glioma , cancer research , biology , cell culture , angiogenesis , immunology , microbiology and biotechnology , inflammation , genetics
Despite decades of research, glioblastoma multiforme ( GBM ) remains a uniformly lethal brain tumor. Transforming growth factor‐, in concert with glioma associated microglia ( GAMS ), promotes GBM growth and invasion. Although TGF‐ has a significant role in GBM progression, failed clinical trials suggest a complex role in GBM pathogenesis similar to non‐CNS cancer. Thus, an improved understanding of the TGF‐ /GAM axis is critical to refine the therapeutic approach toward precise molecular targets. Olfactomedin‐like 3 ( OLFML3 ), a novel secreted glycoprotein, is elevated 9‐fold in GBM. Although poorly studied within the context of GBM, OLFML3 contributes to non‐CNS tumor progression via increased angiogenesis and cell growth pathways. Importantly, Olfml3 has been identified in mice as a direct target gene of TGF‐ in microglia. Therefore,we hypothesized that microglia‐derived Olfml3 polarizes microglia cells toward a pro‐tumorigenic phenotype and promotes tumor cell growth kinetics. We first demonstrated that Olfml3 is a direct target gene of all three TGF‐ isoforms in microglia, but not a mouse glioma cell line (GL261). Using CRISPR/Cas9, we generated an Olfml3 ‐knockout ( Olfml3 ‐/‐ ) microglial cell line. Loss of Olfml3 altered microglial production of several pro‐tumorigenic molecules. Most notably, secretion of key pro‐tumorigenic molecules GM‐CSF, IL‐6, and CSF‐1, was attenuated in Olfml3 ‐/‐ microglia. Additionally, loss of Olfml3 attenuated microglia chemotaxis. Importantly, the effects of OLFML3 were non‐cell autonomous. Following 48‐hour treatment with increasing concentrations of rOLFML3, we observed a linear increase in migration of GL261. However, only a single concentration of rOLFML3 increased GL261 invasion, suggesting a concentration‐dependent cellular response. In conclusion, Olfml3 is a direct target gene of TGF‐ in microglia, but not in glioma cells, suggesting that increased OLFML3 in human GBM may be microglia‐derived. OLFML3 supports glioma progression via pro‐tumorigenic microglia gene expression and promotion of glioma cell malignant phenotype. Further studies aim to elucidate microglia derived OLFML3 and its role in GBM progression in vivo .