Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas.
Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas.
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DOI：
10.1093/procel/pwac006
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发表时间：
2023-03-16
期刊：
影响因子：
21.1
通讯作者：
Zhou, Yan
中科院分区：
文献类型：
--
作者：
Wang, Fangyu;Liu, Xuan;Li, Shaowen;Zhao, Chen;Sun, Yumei;Tian, Kuan;Wang, Junbao;Li, Wei;Xu, Lichao;Jing, Jing;Wang, Juan;Evans, Sylvia M.;Li, Zhiqiang;Liu, Ying;Zhou, Yan
关键词：
多形性胶质母细胞瘤（GBM）是一种高度恶性、异质性的脑肿瘤，含有多种类型的肿瘤细胞和非肿瘤细胞。 GBM细胞是否可以转分化为非神经细胞类型，包括壁细胞或内皮细胞（EC）以支持肿瘤生长和侵袭仍然存在争议。在这里，我们在免疫活性小鼠大脑中从头生成了两个遗传 GBM 模型，模仿人类 GBM 的基本病理和分子特征。谱系追踪和移植研究表明，尽管 GBM 大脑中的血管经历了剧烈的重塑，但几乎没有检测到 GBM 细胞转分化为血管细胞的证据。有趣的是，GBM 细胞在胶质瘤发生过程中可以混杂地表达壁细胞的标记物。此外，单细胞RNA测序表明，壁细胞和EC的拷贝数变异（CNV）模式与GBM细胞不同，表明GBM细胞和血管成分的不同起源。重要的是，人类 GBM 标本的单细胞 CNV 分析也表明 GBM 细胞和血管细胞可能是不同的谱系。血管细胞不是由于转分化而扩张，而是在肿瘤发生期间通过增殖而扩张。因此，胶质瘤发生过程中不太可能发生GBM细胞的跨谱系转分化。我们的研究结果促进了对胶质瘤发生过程中细胞谱系动力学的理解，并对 GBM 的靶向治疗具有影响。
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.
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影响因子：
23.9
作者：
Guimarães-Camboa N;Cattaneo P;Sun Y;Moore-Morris T;Gu Y;Dalton ND;Rockenstein E;Masliah E;Peterson KL;Stallcup WB;Chen J;Evans SM
通讯作者：
Evans SM
影响因子：
64.5
作者：
Ginsberg M;James D;Ding BS;Nolan D;Geng F;Butler JM;Schachterle W;Pulijaal VR;Mathew S;Chasen ST;Xiang J;Rosenwaks Z;Shido K;Elemento O;Rabbany SY;Rafii S
通讯作者：
Rafii S
影响因子：
50.3
作者：
Hara T;Chanoch-Myers R;Mathewson ND;Myskiw C;Atta L;Bussema L;Eichhorn SW;Greenwald AC;Kinker GS;Rodman C;Gonzalez Castro LN;Wakimoto H;Rozenblatt-Rosen O;Zhuang X;Fan J;Hunter T;Verma IM;Wucherpfennig KW;Regev A;Suvà ML;Tirosh I
通讯作者：
Tirosh I
影响因子：
7.7
作者：
Bersini, Simone;Schulte, Roberta;Hetzer, Martin W.
通讯作者：
Hetzer, Martin W.
影响因子：
46.9
作者：
Gao R;Bai S;Henderson YC;Lin Y;Schalck A;Yan Y;Kumar T;Hu M;Sei E;Davis A;Wang F;Shaitelman SF;Wang JR;Chen K;Moulder S;Lai SY;Navin NE
通讯作者：
Navin NE