1. Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma
- Author
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Nakho Chang, Francesca Pia Caruso, Jong Bae Park, Do-Hyun Nam, Michael Lim, Ho Jun Seol, Donggeon Kim, Jung Il Lee, Jeongwu Lee, Seok Chung, Jinlong Yin, Amy B. Heimberger, Young-Taek Oh, Luigi Cerulo, Hye Won Lee, Roel G.W. Verhaak, Qianghu Wang, Antonio Iavarone, Hyun Goo Woo, Nam Gu Her, Hye Mi Kim, Jin-Ho Kim, Woong-Yang Park, Yeri Lee, Jason K. Sa, Da Eun Jeong, Doo Sik Kong, Sung-Soo Kim, Byeongkwi Min, Michele Ceccarelli, Hyunho Kim, Hee Jin Cho, Mijeong Lee, Hye Jin Kim, Erik P. Sulman, Sa, J. K., Chang, N., Lee, H. W., Cho, H. J., Ceccarelli, M., Cerulo, L., Yin, J., Kim, S. S., Caruso, F. P., Lee, M., Kim, D., Oh, Y. T., Lee, Y., Her, N. -G., Min, B., Kim, H. -J., Jeong, D. E., Kim, H. -M., Kim, H., Chung, S., Woo, H. G., Lee, J., Kong, D. -S., Seol, H. J., Lee, J. -I., Kim, J., Park, W. -Y., Wang, Q., Sulman, E. P., Heimberger, A. B., Lim, M., Park, J. B., Iavarone, A., Verhaak, R. G. W., and Nam, D. -H.
- Subjects
lcsh:QH426-470 ,Carcinogenesis ,Mesenchymal Glioblastoma ,Biology ,Mice ,Cell Line, Tumor ,Glioma ,Tumor-Associated Macrophages ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Gene Regulatory Networks ,lcsh:QH301-705.5 ,PI3K/AKT/mTOR pathway ,Neurofibromin 1 ,Macrophages ,Stem Cells ,Research ,Mesenchymal stem cell ,Prognosis ,medicine.disease ,Phenotype ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Macrophage receptor with collagenous structure ,lcsh:Genetics ,lcsh:Biology (General) ,Cancer research ,biology.protein ,Immunotherapy ,Stem cell ,Glioblastoma ,Transcriptome - 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.
- Published
- 2020