Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Lingxiang Wu, Wei Wu, Junxia Zhang, Zheng Zhao, Liangyu Li, Mengyan Zhu, Min Wu, Fan Wu, Fengqi Zhou, Yuxin Du, Rui Chao Chai, Wei Zhang, Xiaoguang Qiu, Quanzhong Liu, Ziyu Wang, Jie Li, Kening Li, Apeng Chen, Yinan Jiang, Xiangwei XiaoHan Zou, Rashmi Srivastava, Tingting Zhang, Yun Cai, Yuan Liang, Bin Huang, Ruohan Zhang, Fan Lin, Lang Hu, Xiuxing Wang, Xu Qian, Sali Lv, Baoli Hu, Siyuan Zheng, Zhibin Hu, Hongbing Shen, Yongping You, Roel G.W. Verhaak, Tao Jiang, Qianghu Wang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prog-nosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM’s natural evolutionary trajectory by using rare multifocal sam-ples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. SIGNIFICANCE: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration.

Original languageEnglish (US)
Pages (from-to)2820-2837
Number of pages18
JournalCancer Discovery
Issue number12
StatePublished - Dec 1 2022

ASJC Scopus subject areas

  • Oncology


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