Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas.

Fangyu Wang; Xuan Liu; Shaowen LI; Chen Zhao; Yumei Sun; Kuan Tian; Junbao Wang; Wei LI; Lichao XU; Jing Jing; Juan Wang; Sylvia M Evans; Zhiqiang LI; Ying Liu; Yan Zhou

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Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas.

Author: Fangyu WANG ¹ ; Xuan LIU ¹ ; Shaowen LI ¹ ; Chen ZHAO ¹ ; Yumei SUN ¹ ; Kuan TIAN ¹ ; Junbao WANG ¹ ; Wei LI ¹ ; Lichao XU ¹ ; Jing JING ¹ ; Juan WANG ² ; Sylvia M EVANS ³ ; Zhiqiang LI ¹ ; Ying LIU ¹ ; Yan ZHOU ¹
Author Information

1. Department of Neurosurgery, Zhongnan hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, The RNA Institute, College of Life Sciences, Wuhan University, Wuhan 430071, China.
2. Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
3. Skaggs School of Pharmacy, Department of Medicine, Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
Publication Type:Journal Article
Keywords: copy number variation; endothelial cells; glioblastoma; lineage tracing; mural cells; single-cell sequencing; trans-differentiation
MeSH: Mice; Animals; Humans; Glioblastoma/pathology*; Endothelial Cells/pathology*; DNA Copy Number Variations; Brain/metabolism*; Brain Neoplasms/pathology*
From: Protein & Cell 2023;14(2):105-122
CountryChina
Language:English
Abstract: Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.