Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma

Yiyun Chen; Ran Huo; Weirong Kang; Yuwei Liu; Zheng Zhao; Weilun Fu; Ruochen Ma; Xiaomeng Zhang; Jihong Tang; Zhihan Zhu; Qingyang Lyu; Yi Huang; Mengli Yan; Biaobin Jiang; Ruichao Chai; Zhaoshi Bao; Zheng Hu; Weiping Wang; Tao Jiang; Yong Cao; Jiguang Wang

doi:10.1016/j.xcrm.2023.101177

Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma

Cell Rep Med. 2023 Sep 19;4(9):101177. doi: 10.1016/j.xcrm.2023.101177. Epub 2023 Aug 30.

Authors

Yiyun Chen¹, Ran Huo², Weirong Kang³, Yuwei Liu³, Zheng Zhao⁴, Weilun Fu², Ruochen Ma⁵, Xiaomeng Zhang⁵, Jihong Tang⁵, Zhihan Zhu⁵, Qingyang Lyu³, Yi Huang³, Mengli Yan⁵, Biaobin Jiang⁵, Ruichao Chai⁶, Zhaoshi Bao⁷, Zheng Hu⁸, Weiping Wang⁹, Tao Jiang¹⁰, Yong Cao¹¹, Jiguang Wang¹²

Affiliations

¹ Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China.
² Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China.
³ Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China.
⁴ Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
⁵ Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁶ Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
⁷ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
⁸ SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁹ Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China. Electronic address: wangwp@hku.hk.
¹⁰ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. Electronic address: taojiang1964@163.com.
¹¹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China. Electronic address: caoyong@bjtth.org.
¹² Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China. Electronic address: jgwang@ust.hk.

Abstract

The role of brain immune compartments in glioma evolution remains elusive. We profile immune cells in glioma microenvironment and the matched peripheral blood from 11 patients. Glioblastoma exhibits specific infiltration of blood-originated monocytes expressing epidermal growth factor receptor (EGFR) ligands EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (p = 0.019), while co-occurring with mesenchymal subtype (p = 4.7 × 10^-7) and marking worse prognosis (p = 0.004 and 0.032 in two cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveal association between elevated TAMo and glioma mesenchymal transformation. Further analyses identify FOSL2 as a TAMo master regulator and demonstrates that FOSL2-EREG/AREG-EGFR signaling axis promotes glioma invasion in vitro. Collectively, we identify TAMo in tumor microenvironment and reveal its driving role in activating EGFR signaling to shape glioma evolution.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain
ErbB Receptors / genetics
Glioblastoma* / genetics
Glioma* / genetics
Humans
Monocytes
Tumor Microenvironment / genetics

Substances

ErbB Receptors
EGFR protein, human