American Association for Cancer Research
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Figure S1, Figure S2, Figure S3, Figure S4, Figure S5, Figure S6, Figure S7, Table S1, Table S2, Table S3, Table S4 from Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment

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posted on 2023-03-31, 02:24 authored by Qi Zhao, Alexandra Eichten, Asma Parveen, Christina Adler, Ying Huang, Wei Wang, Yueming Ding, Alexander Adler, Thomas Nevins, Min Ni, Yi Wei, Gavin Thurston

Figure S1, Heart endothelial cell subpopulations. Figure S2, Expression of selected genes that could distinguish EC subpopulations in heart. Figure S3, Composition of COLO205 tumor stromal cells. Figure S4, Subpopulations of tumor endothelial cells. Figure S5, Gene ontology annotation and pathway enrichment analyses on differentially. expressed genes between anti-angiogenic drug vs. hFc treatment in tip-like cells. Figure S6, Subpopulations in COLO205-derived TAFs. Figure S7, Subpopulations in heart-derived stromal fibroblasts. Table S1, Top 90 genes by ANOVA test p value that have distinctive expression pattern among heart endothelial cell subpopulations. Table S2, Top 30 genes that have distinctive expression pattern in heart EC subpopulations. Table S3, Comparison between overlapping endothelial subpopulation markers identified in heart and tumor tissue. Table S4, Changes of tumor endothelial cells expressing cell cycle genes following anti-angiogenic treatment.

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ARTICLE ABSTRACT

Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition, and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell-cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts responded to antiangiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to antiangiogenic therapies.Significance: These findings provide a framework for defining subpopulations of endothelial cells and tumor-associated fibroblasts and their rapid changes in gene expression following antiangiogenic treatment. Cancer Res; 78(9); 2370–82. ©2018 AACR.

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