Single-Cell Transcriptomics of Endothelial Cells in Upper and Lower Human Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a type of progressive and distant metastatic tumor. Targeting anti-angiogenic genes could effectively hinder ESCC development and metastasis, whereas ESCC locating on the upper or the lower esophagus showed different response to the same clinical treatment, suggesting ESCC location should be taken into account when exploring new therapeutic targets. In the current study, to find novel anti-angiogenic therapeutic targets, we identified endothelial cell subsets in upper and lower human ESCC using single-cell RNA sequencing (scRNA-seq), screened differentially expressed genes (DEGs), and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The results showed that common DEGs shared in the upper and the lower endothelial cells mainly are involved in vessel development, angiogenesis, and cell motility of endothelial cells by regulating PI3K-AKT, Rap1, Ras, TGF-beta, and Apelin signaling pathways. The critical regulatory genes were identified as ITGB1, Col4A1, Col4A2, ITGA6, LAMA4, LAMB1, LAMC1, VWF, ITGA5, THBS1, PDGFB, PGF, RHOC, and CTNNB1. Cell metabolism-relevant genes, e.g., MGST3, PNP, UPP1, and HYAL2 might be the prospective therapeutic targets. Furthermore, we found that DEGs only in the upper endothelial cells, such as MAPK3, STAT3, RHOA, MAPK11, HIF1A, FGFR1, GNG5, GNB1, and ARHGEF12, mainly regulated cell adhesion, structure morphogenesis, and motility through Phospholipase D, Apelin, and VEGF signaling pathways. Moreover, DEGs only in the lower endothelial cells, for instance PLCG2, EFNA1, CALM1, and RALA, mainly regulated cell apoptosis and survival by targeting calcium ion transport through Rap1, Ras, cAMP, Phospholipase D, and Phosphatidylinositol signaling pathways. In addition, the upper endothelial cells showed significant functional diversity such as cytokine-responsive, migratory, and proliferative capacity, presenting a better angiogenic capacity and making it more sensitive to anti-angiogenic therapy compared with the lower endothelial cells. Our study has identified the potential targeted genes for anti-angiogenic therapy for both upper and lower ESCC, and further indicated that anti-angiogenic therapy might be more effective for upper ESCC, which still need to be further examined in the future.

Dynamic profiling of medulloblastoma surfaceome

“…As a member of the integrin family, ITGA5 has been shown to play a regulatory role in tumor cell proliferation, migration, invasion, ECM remodeling, angiogenesis, therapy evasion and modulating immune infiltration across multiple cancer types and models including other types of brain tumors [ 26 , 27 , 30 , 46 , 47 ]. We attribute recurrent-specific markers such as ITGA5 as likely to target tumor subpopulations that are responsible for tumor metastatic programs, angiogenic features, and those that are prone to exhibit therapy evasion with increased self-renewal capacities as identified in our in vitro self-renewal assays [ 46 ]. However, further investigation is needed to elucidate the exact mechanisms behind these programs in Group 3 MB.…”

Plasma protein changes reflect colorectal cancer development and associated inflammation

“…ARHGEF12, also known as leukemia-associated Rho guanine-nucleotide exchange factor (LARG), is underexpressed in CRC tissue and is associated with reduced cell proliferation and a slower migration rate in cancer cells ( 61 ). Moreover, it was found that ARHGEF12 regulates cell adhesion and structure morphogenesis in esophageal squamous cell carcinoma tissues ( 62 ) and plays a key role in erythroid regeneration after chemotherapy in acute lymphoblastic leukemia patients ( 63 ). These proteins can be potentially used as an oncogenic protein signature for CRC diagnosis in plasma.…”

Expression of Prostaglandin Genes and β-Catenin in Whole Blood as Potential Markers of Muscle Degeneration

“…β-catenin is encoded by the CTNNB1B gene, so-called protein moonlight, which means that its cellular functions may be radically different, from the adhesion to signaling role [ 16 ]. Nevertheless, the majority of prior studies, including its relationship with prostaglandin signaling, have focused on the oncological role of β-catenin [ 17 , 18 , 19 , 20 ].…”