Journal Article

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

Caruso, Francesca P., Kim, Donggeon, Sa, Jason K., Iavarone, Antonio, Kim, Sung Soo, Her, Nam-Gu, Kim, Hye-Mi, Oh, Young Taek, Heimberger, Amy B., Park, Jong Bae, Ceccarelli, Michele, Kim, Hyunho, Chung, Seok, Sulman, Erik P., Kim, Jinho, Kim, Hye-Jin, Chang, Nakho, Wang, Qianghu, Cho, Hee Jin, Nam, Do-Hyun, Cerulo, Luigi, Kong, Doo-Sik, Jeong, Da Eun, Seol, Ho Jun, Lee, Jung-Il, Min, Byeongkwi, Verhaak, Roel G. W., Park, Woong-Yang, Lim, Michael, Woo, Hyun Goo, Yin, Jinlong, Lee, Mijeong, Lee, Jeongwu, Lee, Yeri, Lee, Hye Won

2020

Overview

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. MARCO high 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. MARCO high 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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Animal Genetics and Genomics / Bioinformatics / Biomedical and Life Sciences / blood / Brain cancer / Brain tumors / Collagen / Evolutionary Biology / Gene expression / gene expression regulation / genes / Genomics / Glioblastoma / Glioma / Glioma cells / Human Genetics / immunosuppression / Immunotherapy / irradiation / Life Sciences / Macrophages / Malignancy / MARCO protein / Medical prognosis / Mesenchyme / Metastases / Microbial Genetics and Genomics / Neurofibromin 1 / pathogenesis / Peripheral blood / phenotype / Phenotypes / phenotypic plasticity / Plant Genetics and Genomics / prognosis / Radiation / Rapamycin / Recruitment / Stem cells / Survival analysis / TOR protein / Transcription / transcription (genetics) / Treatment resistance / Tumors