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

Goveia, Jermaine; Rohlenová, Kateřina; Taverna, Federico; Treps, Lucas; Conradi, Lena‐Christin; Pircher, Andreas; Geldhof, Vincent; Rooij, Laura P.M.H. de; Kalucka, Joanna; Sokol, Liliana; García-Caballero, Melissa; Zheng, Yingfeng; Qian, Junbin; Teuwen, Laure-Anne; Khan, Shawez; Boeckx, Bram; Wauters, Els; Decaluwé, Herbert; Leyn, Paul De; Vansteenkiste, Johan; Weynand, Birgit; Sagaert, Xavier; Verbeken, Erik; Wolthuis, Albert; Topal, Baki; Everaerts, Wouter; Bohnenberger, Hanibal; Emmert, Alexander; Panovska, Dena; Smet, Frederik De; Staal, Frank J. T.; McLaughlin, René; Impens, Francis; Lagani, Vincenzo; Vinckier, Stefan; Mazzone, Massimiliano; Schoonjans, Luc; Dewerchin, Mieke; Eelen, Guy; Karakach, Tobias K.; Yang, Huanming; Wang, Jian; Bolund, Lars; Lin, Lin; Thienpont, Bernard; Li, Xuri; Lambrechts, Diether; Luo, Yonglun; Carmeliet, Peter

doi:10.1016/j.ccell.2020.03.002

Cited by 121 publications

(260 citation statements)

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“…Consistent with the impaired tip cell phenotype, radial expansion of the vascular network was significantly inhibited in the Pdcd10 -ko retina ( Figure 5I , quantification in Figure 5J ). It remains to be explored whether these tip-like cells have features of the recently described breach cells of lung tumor vessels ( Goveia et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Orsenigo

Conze

Jauhiainen

et al. 2020

eLife

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Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, KRIT1, CCM2, and PDCD10 (CCM3). Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells (ECs) under both normal conditions and after deletion of Pdcd10 (Ccm3) in a mouse model of CCM. Integrated single-cell analysis identifies arterial ECs as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary ECs and respective resident endothelial progenitors appear to be at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level.

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Section: Resultsmentioning

confidence: 99%

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Orsenigo

Conze

Jauhiainen

et al. 2020

eLife

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“…Recent scRNA‐seq studies have determined that tumor endothelial cells are heterogeneous at a molecular level, and that the various subtypes contribute to angiogenesis and tumor progression and respond to targeting therapies in different ways 90‐92 . Detailed subtyping and a deeper understanding of this heterogeneity would require an extensive functional validation study, but would be helpful in establishing new therapeutic strategies beyond VEGF targeting.…”

Section: Endothelial Cellsmentioning

confidence: 99%

Tumor microenvironment in gastric cancers

2020

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The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer‐associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R‐spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor‐promoting and tumor‐restraining populations. Among immune cell populations, tumor‐associated macrophages, including M1 and M2 macrophages, and myeloid‐derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling new therapeutic targets.

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“…To further characterize the SARS-CoV-2 entry factor transcript expression patterns in brain endothelial cells, we examined the different brain endothelial cell clusters according to their arterio-venous specification, as previously described in mouse brain 78–80 (Figure 4a). We found that CTSB was expressed in multiple brain endothelial cell types including veins, capillaries, endothelial cells 1 (EC1), antigen presenting- and vein (antigen presenting) endothelial cells (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, recent studies using single-cell transcriptomics in human and mouse tissues revealed endothelial clusters in a variety of tissues including the human bladder, and kidney (and others) as well as the mouse and human lung expressing MCH class II genes such as HLA-DPA1 and HLA-DRA involved in MHC class II- mediated antigen processing, loading and presentation 80 .…”

Section: Resultsmentioning

confidence: 99%

The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors

Ghobrial

Charish

Takada

et al. 2020

Preprint

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A large number of hospitalized COVID-19 patients show neurological symptoms such as ischemic- and hemorrhagic stroke as well as encephalitis, and SARS-CoV-2 can directly infect endothelial cells leading to endotheliitis across multiple vascular beds. These findings suggest an involvement of the brain- and peripheral vasculature in COVID-19, but the underlying molecular mechanisms remain obscure. To understand the potential mechanisms underlying SARS-CoV-2 tropism for brain vasculature, we constructed a molecular atlas of the expression patterns of SARS-CoV-2 viral entry-associated genes (receptors and proteases) and SARS-CoV-2 interaction partners in human (and mouse) adult and fetal brain as well as in multiple non-CNS tissues in single-cell RNA-sequencing data across various datasets. We observed a distinct expression pattern of the cathepsins B (CTSB) and -L (CTSL) - which are able to substitute for the ACE2 co-receptor TMPRSS2 - in the human vasculature with CTSB being mainly expressed in the brain vasculature and CTSL predominantly in the peripheral vasculature, and these observations were confirmed at the protein level in the Human Protein Atlas and using immunofluorescence stainings. This expression pattern of SARS-CoV-2 viralentry associated proteases and SARS-CoV-2 interaction partners was also present in endothelial cells and microglia in the fetal brain, suggesting a developmentally establishedSARS-CoV-2 entry machinery in the human vasculature. At both the adult and fetal stages, we detected a distinct pattern of SARS-CoV-2 entry associated genes' transcripts in brain vascular endothelial cells and microglia, providing a potential explanation for an inflammatory response in the brain endothelium upon SARS-CoV-2 infection. Moreover, CTSB was co-expressed in adult and fetal brain endothelial cells with genes and pathways involved in innate immunity and inflammation, angiogenesis, blood-brain-barrier permeability, vascular metabolism, and coagulation, providing a potential explanation for the role of brain endothelial cells in clinically observed (neuro)vascular symptoms in COVID-19 patients. Our study serves as a publicly available single-cell atlas of SARS-CoV-2 related entry factors and interaction partners in human and mouse brain endothelial- and perivascular cells, which can be employed for future studies in clinical samples of COVID-19 patients.

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

Abstract: In the original article, the surname of co-author Wouter Everaerts was spelled incorrectly as "Everaert." It appears correctly in this Correction, and the error has been corrected online.

Cited by 121 publications

References 0 publications

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Tumor microenvironment in gastric cancers

The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors

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