Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
Bibliographical noteFunding Information:
This work was supported by grants from the Korea Health Technology R&D through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1A2B4011780), National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (NRF-2016R1A5A2945889, NRF-2020R1F1A1076444), Basic Research Lab Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science (NRF-2018R1A4A1025860), National Cancer Center, Republic of Korea (NCC-1810121, NCC-1810861), National Institutes of Health grants (P50 CA127001, R01 CA190121, P01 CA085878), Associazione Italiana per la Ricerca sul Cancro (AIRC) under IG 2018 - ID. 21846 project to MC, Cancer Prevention & Research Institute of Texas (R140606), National Brain Tumor Association Defeat GLIOBLASTOMA project, and the National Brain Tumor Association Oligo Research Fund.
© 2020 The Author(s).
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Cell Biology