Year: 2025
Type: article
Abstract: Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.
Source: JCI Insight
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Awards: A Novel Adenoviral-Permissive, Immunocompetent Hamster Model to Evaluate Oncolytic Adenoviral Therapy for Glioblastoma, Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems, G1637196319, G2611891551, Graduate Research Fellowship Program (GRFP), G380820829, G4583515593, G5212140461, MSC-Derived Exosomes and MicroRNA in Glioma Therapy, Graduate Research Fellowship Program (GRFP), G7438924782, LTQ XL Linear Quadrupole Ion Trap Mass Spectrometer, G8751405378, G8824410243, G9000174336, Cancer Center Support Grant, Mechanisms of adhesion and invasion in hyaluronic acid matrices, Cancer Center Support Grant, Retroviral RLI immunomodulatory gene therapy for glioblastoma, SPORE in Brain Cancer
OpenAlex ID: W4413637113