An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates.,Cancer Cell

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An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-01-13 , DOI: 10.1016/j.ccell.2019.12.001
Jermaine Goveia ₁ , Katerina Rohlenova ₁ , Federico Taverna ₁ , Lucas Treps ₁ , Lena-Christin Conradi ₁ , Andreas Pircher ₁ , Vincent Geldhof ₁ , Laura P M H de Rooij ₁ , Joanna Kalucka ₁ , Liliana Sokol ₁ , Melissa García-Caballero ₁ , Yingfeng Zheng ₂ , Junbin Qian ₃ , Laure-Anne Teuwen ₁ , Shawez Khan ₁ , Bram Boeckx ₃ , Els Wauters ₄ , Herbert Decaluwé ₅ , Paul De Leyn ₅ , Johan Vansteenkiste ₄ , Birgit Weynand ₆ , Xavier Sagaert ₆ , Erik Verbeken ₆ , Albert Wolthuis ₇ , Baki Topal ₇ , Wouter Everaerts ₈ , Hanibal Bohnenberger ₉ , Alexander Emmert ₁₀ , Dena Panovska ₁₁ , Frederik De Smet ₁₁ , Frank J T Staal ₁₂ , Rene J Mclaughlin ₁₂ , Francis Impens ₁₃ , Vincenzo Lagani ₁₄ , Stefan Vinckier ₁ , Massimiliano Mazzone ₁₅ , Luc Schoonjans ₁ , Mieke Dewerchin ₁ , Guy Eelen ₁ , Tobias K Karakach ₁ , Huanming Yang ₁₆ , Jian Wang ₁₆ , Lars Bolund ₁₇ , Lin Lin ₁₇ , Bernard Thienpont ₁₈ , Xuri Li ₂ , Diether Lambrechts ₃ , Yonglun Luo ₁₉ , Peter Carmeliet ₂₀

Affiliation

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, Leuven 3000, Belgium.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.
Laboratory of Translational Genetics, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, Leuven 3000, Belgium.
Respiratory Oncology Unit (Respiratory Medicine) and Leuven Lung Cancer Group, University Hospitals Leuven, Leuven 3000, Belgium.
Respiratory Oncology Unit (Respiratory Medicine) and Leuven Lung Cancer Group, University Hospitals Leuven, Leuven 3000, Belgium; Department of Thoracic Surgery, University Hospitals Leuven, Leuven 3000, Belgium.
Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium.
Department of Abdominal Surgery, University Hospitals Leuven, Leuven 3000, Belgium.
Laboratory for Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven 3000, Belgium; Department of Urology, University Hospitals Leuven, Leuven 3000, Belgium.
Institute of Pathology, University Medical Center, Göttingen 37075, Germany.
Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen 37075, Germany.
Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium.
Department of Immunology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
VIB Proteomics Core and VIB Center for Medical Biotechnology, Ghent 9000, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium.
Institute of Chemical Biology, Ilia State University, Tbilisi 0162, Georgia; Gnosis Data Analysis PC, Heraklion GR-700 13, Greece.
Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, Leuven 3000, Belgium.
BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China.
Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China.
Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China; Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China.
Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.

Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.

中文翻译：

一种综合的基因表达景观分析方法，用于鉴定肺肿瘤内皮细胞异质性和血管生成候选物。

跨患者，物种（人类/小鼠）和模型（体内/体外）的肺肿瘤内皮细胞（TEC）表型的异质性在单细胞水平上仍存有不足。我们从人/小鼠（周）肿瘤肺和培养的人肺TEC中对单细胞RNA（scRNA）排序的56,771内皮细胞进行了测序，并检测了17种已知和16种以前无法识别的表型，包括推定调节免疫监视的TEC。我们将规范的尖端TECs解析为已知的迁移尖端和假定的基底膜重塑突破表型。尖端TEC信号与患者生存率相关，尖端/破裂TEC对血管内皮生长因子的阻断最为敏感。只有尖端TECs在物种/模型之间是一致的，并且共享保守的标记。

更新日期：2020-01-13

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