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

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

doi:10.1016/j.ccell.2019.12.001

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

240 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	21-36.e13
Journal	Cancer Cell
Volume	37
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2019.12.001
State	Published - Jan 13 2020

Bibliographical note

Funding Information:
We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G., K.R., L.T., and J.K. are supported by the ‘ Fonds Wetenschappelijk Onderzoek ’ (FWO); L.-C.C. by the Else Kröner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund ( J3730-B26 ); L.-A.T. by Antwerp University ; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society ); M.M. by Methusalem funding ( Flemish Government ); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen ( SZSM201612074 ); L.L. by Lundbeck Foundation ( R219–2016-1375 ) and DFF Sapere Aude Starting grant ( 8048-00072A ); Y.L. by BGI -Research, Danish Research Council for Independent Research ( DFF–1337–00128 ), Sapere Aude Young Research Talent Prize ( DFF-1335–00763A ), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology , Zhongshan Ophthalmic Center ( Sun Yat-sen University ) and National Natural Science Foundation of China ( 81670855 ), Key Program of Guangzhou Scientific Research Plan ( 3030901006074 ); and P.C. by VIB TechWatch , Methusalem funding, FWO, Foundation against Cancer ( 2016-078 ), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept ( ERC-713758 ), and Advanced ERC Research Grant ( EU-ERC743074 ).

Funding Information:
We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G. K.R. L.T. and J.K. are supported by the ‘Fonds Wetenschappelijk Onderzoek’ (FWO); L.-C.C. by the Else Kröner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund (J3730-B26); L.-A.T. by Antwerp University; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society); M.M. by Methusalem funding (Flemish Government); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen (SZSM201612074); L.L. by Lundbeck Foundation (R219–2016-1375) and DFF Sapere Aude Starting grant (8048-00072A); Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF–1337–00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center (Sun Yat-sen University) and National Natural Science Foundation of China (81670855), Key Program of Guangzhou Scientific Research Plan (3030901006074); and P.C. by VIB TechWatch, Methusalem funding, FWO, Foundation against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept (ERC-713758), and Advanced ERC Research Grant (EU-ERC743074). J.G. K.R. F.T. and L.T. designed and analyzed experiments. J.G. L.T. L.-C.C. A.P. J.K. and M.G-C. set up the EC isolation protocols. L.-C.C. E.W. H.D, P.DL. J.V. B.W. X.S. E.V. A.W. B. Topal, W.E. H.B. and A.E. provided human tumor samples. K.R. L.T. L.-C.C. V.G. J.K. L. Sokol, J.Q, and L.-A.T. prepared the scRNA-seq samples. L.L. B. Thienpont, D.L. and Y.L. did 10× single-cell sequencing. S.K. B.B. and T.K. processed scRNA-seq data. L.dR. J.K. D.P. F.D.S. F.J.T.S. R.J.M. and Y.Z. did CyTOF. L.T. J.K. and S.V. did immunohistochemistry. F.I. did proteomics analysis. V.L. provided advice on the statistical methodology. F.D.S. M.M. G.E. M.D. L. Schoonjans, H.Y. J.W. L.B. L.L. B. Thienpont, X.L. D.L. and Y.L. provided advice and discussed the results. J.G. K.R. and P.C. wrote the manuscript. P.C. conceptualized the study. All authors discussed the results and the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

angiogenesis
anti-angiogenic therapy
cancer
endothelial cells
endothelial heterogeneity
multi-omics
single-cell RNA sequencing

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2019.12.001

Cite this

Goveia, J., Rohlenova, K., Taverna, F., Treps, L., Conradi, L. C., Pircher, A., Geldhof, V., de Rooij, L. P. M. H., Kalucka, J., Sokol, L., García-Caballero, M., Zheng, Y., Qian, J., Teuwen, L. A., Khan, S., Boeckx, B., Wauters, E., Decaluwé, H., De Leyn, P., ... Carmeliet, P. (2020). An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates. Cancer Cell, 37(1), 21-36.e13. https://doi.org/10.1016/j.ccell.2019.12.001

@article{c07bb25e3d724deb9816a4a17fdb7da4,

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

abstract = "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.",

keywords = "angiogenesis, anti-angiogenic therapy, cancer, endothelial cells, endothelial heterogeneity, multi-omics, single-cell RNA sequencing",

author = "Jermaine Goveia and Katerina Rohlenova and Federico Taverna and Lucas Treps and Conradi, {Lena Christin} and Andreas Pircher and Vincent Geldhof and {de Rooij}, {Laura P.M.H.} and Joanna Kalucka and Liliana Sokol and Melissa Garc{\'i}a-Caballero and Yingfeng Zheng and Junbin Qian and Teuwen, {Laure Anne} and Shawez Khan and Bram Boeckx and Els Wauters and Herbert Decaluw{\'e} and {De Leyn}, Paul and Johan Vansteenkiste and Birgit Weynand and Xavier Sagaert and Erik Verbeken and Albert Wolthuis and Baki Topal and Wouter Everaert and Hanibal Bohnenberger and Alexander Emmert and Dena Panovska and {De Smet}, Frederik and Staal, {Frank J.T.} and Mclaughlin, {Rene J.} and Francis Impens and Vincenzo Lagani and Stefan Vinckier and Massimiliano Mazzone and Luc Schoonjans and Mieke Dewerchin and Guy Eelen and Karakach, {Tobias K.} and Huanming Yang and Jian Wang and Lars Bolund and Lin Lin and Bernard Thienpont and Xuri Li and Diether Lambrechts and Yonglun Luo and Peter Carmeliet",

note = "Funding Information: We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G., K.R., L.T., and J.K. are supported by the {\textquoteleft} Fonds Wetenschappelijk Onderzoek {\textquoteright} (FWO); L.-C.C. by the Else Kr{\"o}ner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund ( J3730-B26 ); L.-A.T. by Antwerp University ; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society ); M.M. by Methusalem funding ( Flemish Government ); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen ( SZSM201612074 ); L.L. by Lundbeck Foundation ( R219–2016-1375 ) and DFF Sapere Aude Starting grant ( 8048-00072A ); Y.L. by BGI -Research, Danish Research Council for Independent Research ( DFF–1337–00128 ), Sapere Aude Young Research Talent Prize ( DFF-1335–00763A ), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology , Zhongshan Ophthalmic Center ( Sun Yat-sen University ) and National Natural Science Foundation of China ( 81670855 ), Key Program of Guangzhou Scientific Research Plan ( 3030901006074 ); and P.C. by VIB TechWatch , Methusalem funding, FWO, Foundation against Cancer ( 2016-078 ), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept ( ERC-713758 ), and Advanced ERC Research Grant ( EU-ERC743074 ). Funding Information: We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G. K.R. L.T. and J.K. are supported by the {\textquoteleft}Fonds Wetenschappelijk Onderzoek{\textquoteright} (FWO); L.-C.C. by the Else Kr{\"o}ner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund (J3730-B26); L.-A.T. by Antwerp University; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society); M.M. by Methusalem funding (Flemish Government); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen (SZSM201612074); L.L. by Lundbeck Foundation (R219–2016-1375) and DFF Sapere Aude Starting grant (8048-00072A); Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF–1337–00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center (Sun Yat-sen University) and National Natural Science Foundation of China (81670855), Key Program of Guangzhou Scientific Research Plan (3030901006074); and P.C. by VIB TechWatch, Methusalem funding, FWO, Foundation against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept (ERC-713758), and Advanced ERC Research Grant (EU-ERC743074). J.G. K.R. F.T. and L.T. designed and analyzed experiments. J.G. L.T. L.-C.C. A.P. J.K. and M.G-C. set up the EC isolation protocols. L.-C.C. E.W. H.D, P.DL. J.V. B.W. X.S. E.V. A.W. B. Topal, W.E. H.B. and A.E. provided human tumor samples. K.R. L.T. L.-C.C. V.G. J.K. L. Sokol, J.Q, and L.-A.T. prepared the scRNA-seq samples. L.L. B. Thienpont, D.L. and Y.L. did 10× single-cell sequencing. S.K. B.B. and T.K. processed scRNA-seq data. L.dR. J.K. D.P. F.D.S. F.J.T.S. R.J.M. and Y.Z. did CyTOF. L.T. J.K. and S.V. did immunohistochemistry. F.I. did proteomics analysis. V.L. provided advice on the statistical methodology. F.D.S. M.M. G.E. M.D. L. Schoonjans, H.Y. J.W. L.B. L.L. B. Thienpont, X.L. D.L. and Y.L. provided advice and discussed the results. J.G. K.R. and P.C. wrote the manuscript. P.C. conceptualized the study. All authors discussed the results and the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2020",

month = jan,

day = "13",

doi = "10.1016/j.ccell.2019.12.001",

language = "English (US)",

volume = "37",

pages = "21--36.e13",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "1",

}

Goveia, J, Rohlenova, K, Taverna, F, Treps, L, Conradi, LC, Pircher, A, Geldhof, V, de Rooij, LPMH, Kalucka, J, Sokol, L, García-Caballero, M, Zheng, Y, Qian, J, Teuwen, LA, Khan, S, Boeckx, B, Wauters, E, Decaluwé, H, De Leyn, P, Vansteenkiste, J, Weynand, B, Sagaert, X, Verbeken, E, Wolthuis, A, Topal, B, Everaert, W, Bohnenberger, H, Emmert, A, Panovska, D, De Smet, F, Staal, FJT, Mclaughlin, RJ, Impens, F, Lagani, V, Vinckier, S, Mazzone, M, Schoonjans, L, Dewerchin, M, Eelen, G, Karakach, TK, Yang, H, Wang, J, Bolund, L, Lin, L, Thienpont, B, Li, X, Lambrechts, D, Luo, Y & Carmeliet, P 2020, 'An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates', Cancer Cell, vol. 37, no. 1, pp. 21-36.e13. https://doi.org/10.1016/j.ccell.2019.12.001

TY - JOUR

T1 - An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates

AU - Goveia, Jermaine

AU - Rohlenova, Katerina

AU - Taverna, Federico

AU - Treps, Lucas

AU - Conradi, Lena Christin

AU - Pircher, Andreas

AU - Geldhof, Vincent

AU - de Rooij, Laura P.M.H.

AU - Kalucka, Joanna

AU - Sokol, Liliana

AU - García-Caballero, Melissa

AU - Zheng, Yingfeng

AU - Qian, Junbin

AU - Teuwen, Laure Anne

AU - Khan, Shawez

AU - Boeckx, Bram

AU - Wauters, Els

AU - Decaluwé, Herbert

AU - De Leyn, Paul

AU - Vansteenkiste, Johan

AU - Weynand, Birgit

AU - Sagaert, Xavier

AU - Verbeken, Erik

AU - Wolthuis, Albert

AU - Topal, Baki

AU - Everaert, Wouter

AU - Bohnenberger, Hanibal

AU - Emmert, Alexander

AU - Panovska, Dena

AU - De Smet, Frederik

AU - Staal, Frank J.T.

AU - Mclaughlin, Rene J.

AU - Impens, Francis

AU - Lagani, Vincenzo

AU - Vinckier, Stefan

AU - Mazzone, Massimiliano

AU - Schoonjans, Luc

AU - Dewerchin, Mieke

AU - Eelen, Guy

AU - Karakach, Tobias K.

AU - Yang, Huanming

AU - Wang, Jian

AU - Bolund, Lars

AU - Lin, Lin

AU - Thienpont, Bernard

AU - Li, Xuri

AU - Lambrechts, Diether

AU - Luo, Yonglun

AU - Carmeliet, Peter

N1 - Funding Information: We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G., K.R., L.T., and J.K. are supported by the ‘ Fonds Wetenschappelijk Onderzoek ’ (FWO); L.-C.C. by the Else Kröner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund ( J3730-B26 ); L.-A.T. by Antwerp University ; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society ); M.M. by Methusalem funding ( Flemish Government ); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen ( SZSM201612074 ); L.L. by Lundbeck Foundation ( R219–2016-1375 ) and DFF Sapere Aude Starting grant ( 8048-00072A ); Y.L. by BGI -Research, Danish Research Council for Independent Research ( DFF–1337–00128 ), Sapere Aude Young Research Talent Prize ( DFF-1335–00763A ), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology , Zhongshan Ophthalmic Center ( Sun Yat-sen University ) and National Natural Science Foundation of China ( 81670855 ), Key Program of Guangzhou Scientific Research Plan ( 3030901006074 ); and P.C. by VIB TechWatch , Methusalem funding, FWO, Foundation against Cancer ( 2016-078 ), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept ( ERC-713758 ), and Advanced ERC Research Grant ( EU-ERC743074 ). Funding Information: We acknowledge K. Peeters, T. Van Brussel, and R. Schepers for assistance. J.G. K.R. L.T. and J.K. are supported by the ‘Fonds Wetenschappelijk Onderzoek’ (FWO); L.-C.C. by the Else Kröner-Fresenius and Fritz Thyssen Stiftung (10.16.2.017MN); A.P. by the Austrian Science Fund (J3730-B26); L.-A.T. by Antwerp University; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); S.K. by Kom op Tegen Kanker (Stand up to Cancer, Flemish Cancer Society); M.M. by Methusalem funding (Flemish Government); L.B. and Y.L. by Sanming Project of Medicine in Shenzhen (SZSM201612074); L.L. by Lundbeck Foundation (R219–2016-1375) and DFF Sapere Aude Starting grant (8048-00072A); Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF–1337–00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR); X.L. by State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center (Sun Yat-sen University) and National Natural Science Foundation of China (81670855), Key Program of Guangzhou Scientific Research Plan (3030901006074); and P.C. by VIB TechWatch, Methusalem funding, FWO, Foundation against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), ERC Proof of Concept (ERC-713758), and Advanced ERC Research Grant (EU-ERC743074). J.G. K.R. F.T. and L.T. designed and analyzed experiments. J.G. L.T. L.-C.C. A.P. J.K. and M.G-C. set up the EC isolation protocols. L.-C.C. E.W. H.D, P.DL. J.V. B.W. X.S. E.V. A.W. B. Topal, W.E. H.B. and A.E. provided human tumor samples. K.R. L.T. L.-C.C. V.G. J.K. L. Sokol, J.Q, and L.-A.T. prepared the scRNA-seq samples. L.L. B. Thienpont, D.L. and Y.L. did 10× single-cell sequencing. S.K. B.B. and T.K. processed scRNA-seq data. L.dR. J.K. D.P. F.D.S. F.J.T.S. R.J.M. and Y.Z. did CyTOF. L.T. J.K. and S.V. did immunohistochemistry. F.I. did proteomics analysis. V.L. provided advice on the statistical methodology. F.D.S. M.M. G.E. M.D. L. Schoonjans, H.Y. J.W. L.B. L.L. B. Thienpont, X.L. D.L. and Y.L. provided advice and discussed the results. J.G. K.R. and P.C. wrote the manuscript. P.C. conceptualized the study. All authors discussed the results and the manuscript. The authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2020/1/13

Y1 - 2020/1/13

N2 - 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.

AB - 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.

KW - angiogenesis

KW - anti-angiogenic therapy

KW - cancer

KW - endothelial cells

KW - endothelial heterogeneity

KW - multi-omics

KW - single-cell RNA sequencing

UR - http://www.scopus.com/inward/record.url?scp=85077569743&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.12.001

DO - 10.1016/j.ccell.2019.12.001

M3 - Article

C2 - 31935371

AN - SCOPUS:85077569743

SN - 1535-6108

VL - 37

SP - 21-36.e13

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this