Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues

Jiayu Zhang; Tong Lu; Shiqi Lu; Shuaijun Ma; Donghui Han; Keying Zhang; Chao Xu; Shaojie Liu; Lunbiao Gan; Xinjie Wu; Fa Yang; Weihong Wen; Weijun Qin

doi:10.1016/j.csbj.2022.12.049

Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues

Comput Struct Biotechnol J. 2022 Dec 30:21:665-676. doi: 10.1016/j.csbj.2022.12.049. eCollection 2023.

Authors

Jiayu Zhang¹, Tong Lu¹, Shiqi Lu², Shuaijun Ma¹, Donghui Han¹, Keying Zhang¹, Chao Xu¹, Shaojie Liu¹, Lunbiao Gan², Xinjie Wu², Fa Yang¹, Weihong Wen², Weijun Qin¹

Affiliations

¹ Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, China.
² Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.

Abstract

Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGF/VEGFR therapy; however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGF/VEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.

Keywords: BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; CRC, Colorectal cancer; ECs, Endothelial cells; Endothelial cells; GC, Gastric cancer; HNSC, Head and Neck squamous cell carcinoma; KICH, Kidney chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LC, Lung cancer; LIHC, Liver hepatocellular carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; OV, Ovarian serous cystadenocarcinoma; OVC, Ovarian cancer; PAAD, Pancreatic adenocarcinoma; PDAC, Pancreatic ductal adenocarcinoma; PRAD, Prostate adenocarcinoma; PSMA, Prostate-specific membrane antigen; RCC, Renal cell carcinoma; READ, Rectum adenocarcinoma; STAD, Stomach adenocarcinoma; Single-cell RNA sequencing; TME, Tumor microenvironment; Tumor microenvironment; VEGF, Vascular endothelial growth factor; scRNA-seq, Single-cell RNA sequencing.