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

• Published in: Genome Biology Vol. 21; no. 1; p. 216
• Main Authors: Sa, Jason K., Chang, Nakho, Lee, Hye Won, Cho, Hee Jin, Ceccarelli, Michele, Cerulo, Luigi, Yin, Jinlong, Kim, Sung Soo, Caruso, Francesca P., Lee, Mijeong, Kim, Donggeon, Oh, Young Taek, Lee, Yeri, Her, Nam-Gu, Min, Byeongkwi, Kim, Hye-Jin, Jeong, Da Eun, Kim, Hye-Mi, Kim, Hyunho, Chung, Seok, Woo, Hyun Goo, Lee, Jeongwu, Kong, Doo-Sik, Seol, Ho Jun, Lee, Jung-Il, Kim, Jinho, Park, Woong-Yang, Wang, Qianghu, Sulman, Erik P., Heimberger, Amy B., Lim, Michael, Park, Jong Bae, Iavarone, Antonio, Verhaak, Roel G. W., Nam, Do-Hyun
• Format: Journal Article
• Language: English
• Published: England BioMed Central 26.08.2020; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; blood; Brain cancer; Brain tumors; Collagen; Gene expression; gene expression regulation; genes; Genomics; Glioblastoma; Glioma; Glioma cells; immunosuppression; Immunotherapy; irradiation; Macrophages; Malignancy; MARCO protein; Medical prognosis; Mesenchyme; Metastases; Neurofibromin 1; pathogenesis; Peripheral blood; phenotype; Phenotypes; phenotypic plasticity; prognosis; Radiation; Rapamycin; Recruitment; Stem cells; Survival analysis; TOR protein; Transcription; transcription (genetics); Treatment resistance; Tumors
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-020-02140-x

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. 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 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 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. 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.