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Theranostics 2023; 13(11):3744-3760. doi:10.7150/thno.81407 This issue Cite

Research Paper

Single-cell RNA sequencing identifies critical transcription factors of tumor cell invasion induced by hypoxia microenvironment in glioblastoma

Yanru Zhang^1,#, Bo Zhang^2,#, Chengqian Lv^3,#, Nan Zhang^4,#, Kaiyuan Xing¹, Zixuan Wang¹, Rongkai Lv¹, Mingchen Yu^5,✉, Chaohan Xu^1,✉, Yihan Wang^1,✉

1. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
2. Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
3. Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
4. College of Life Science and Technology, Huazhong University of Science and Technology, China.
5. Beijing Neurosurgical Institute, Capital Medical University. Beijing 100069, China.
^# These authors contributed equally.

✉ Corresponding author: Yihan Wang, College of Bioinformatics Science and Technology, Harbin Medical University, Email: wangyihanedu.cn; Chaohan Xu, College of Bioinformatics Science and Technology, Harbin Medical University, Email: chaohanxuedu.cn; Mingchen Yu, Beijing Neurosurgical Institute, Capital Medical University, Email: yumcccmu.edu.cn. More

Abstract

Rationale: Glioblastoma (GBM) is an aggressive malignant primary brain cancer with poor survival. Hypoxia is a hallmark of GBM, which promotes tumor cells spreading (invasion) into the healthy brain tissue.

Methods: To better elucidate the influence of hypoxia on GBM invasion, we proposed a data-driven modeling framework for predicting cellular hypoxia (CHPF) by integrating single cell transcriptome profiling and hypoxia gene signatures.

Results: We characterized the hypoxia status landscape of GBM cells and observed that hypoxic cells were only present in the tumor core. Then, by investigating the cell-cell communication between immune cells and tumor cells, we discovered significant interaction between macrophages and tumor cells in hypoxic microenvironment. Notably, we dissected the functional heterogeneity of tumor cells and identified a hypoxic subpopulation that had highly invasive potential. By constructing cell status specific gene regulatory networks, we further identified 14 critical regulators of tumor invasion induced by hypoxic microenvironment. Finally, we confirmed that knocking down two critical regulators CEBPD and FOSL1 could reduce the invasive ability of GBM under hypoxic conditions. Additionally, we revealed the therapeutic effect of Axitinib and Entinostat through the mice model.

Conclusion: Our work revealed the critical regulators in hypoxic subpopulation with high invasive potential in GBM, which may have practical implications for clinical targeted-hypoxia cancer drug therapy.

Keywords: glioblastoma, hypoxia status, invasion, regulators, single-cell RNA sequencing

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