Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma
- PDF / 2,878,578 Bytes
- 17 Pages / 595.276 x 793.701 pts Page_size
- 86 Downloads / 148 Views
RESEARCH
Open Access
Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma Jason K. Sa1† , Nakho Chang2†, Hye Won Lee3†, Hee Jin Cho4†, Michele Ceccarelli5,6†, Luigi Cerulo7, Jinlong Yin8, Sung Soo Kim9,10, Francesca P. Caruso5,11, Mijeong Lee12, Donggeon Kim12, Young Taek Oh13, Yeri Lee12, Nam-Gu Her14, Byeongkwi Min14,15, Hye-Jin Kim14, Da Eun Jeong16, Hye-Mi Kim12, Hyunho Kim17, Seok Chung17, Hyun Goo Woo18,19, Jeongwu Lee20, Doo-Sik Kong21, Ho Jun Seol21, Jung-Il Lee21, Jinho Kim22, Woong-Yang Park15,22, Qianghu Wang23, Erik P. Sulman24, Amy B. Heimberger25, Michael Lim26, Jong Bae Park9,10*, Antonio Iavarone13,27,28*, Roel G. W. Verhaak29* and Do-Hyun Nam12,14,15,21* * Correspondence: [email protected]; [email protected]; roel. [email protected]; [email protected] † Jason K. Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho and Michele Ceccarelli contributed equally to this work. 9 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea 13 Institute for Cancer Genetics, Columbia University, New York, NY, USA 29 The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA 12 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea Full list of author information is available at the end of the article
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 mesenchymalassociated 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.
© The Author(s).
Data Loading...
