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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number216
JournalGenome biology
Volume21
Issue number1
DOIs
StatePublished - Aug 26 2020

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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