Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116+ pericytes in cancer metastasis

IF 29 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-10-10 DOI:10.1038/s41588-025-02341-9

Xiaoya Pei, Zhichao Liu, Lin Tang, Junpeng Zhang, Yan He, Xiaowan Zhuang, Yuxiang Song, Shaocong Peng, Yan He, Yahui Zhao, Xuanzhang Huang, Yiwei Xu, Junyi Li, Liang Peng, Xingyuan Shi, Fan Zhang, Chong Liu, Mingliang He, Wei Dai, Liang Wu, Simon Law, Jinbao Liu, Zhenning Wang, Zhigang Li, Wenwen Xu, Zhihua Liu, Bin Li

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Abstract

Tumor metastasis leads to most cancer deaths. However, how cellular diversity and dynamic cooperation within the tumor microenvironment contribute to metastasis remains poorly understood. Here we leverage single-cell multi-omics (16 samples, 117,169 cells) and spatial transcriptomics (five samples, 195,366 cells) to uncover the cellular and spatial architecture of esophageal squamous cell carcinoma (ESCC), and characterize an immunosuppressive GPR116+ pericyte subset promoting tumor metastasis and immunotherapy resistance. GPR116+ pericyte enrichment is transcriptionally regulated by PRRX1, evidenced by pericyte-specific Prrx1 knockout mice. Mechanistically, GPR116+ pericytes secrete EGFL6 to bind integrin β1 on cancer cells, activating the NF-κB pathway to facilitate metastasis. Serum EGFL6 serves as a noninvasive biomarker for the diagnosis and prognosis of several tumors. Blocking integrin β1 suppresses metastasis and improves immunotherapy response in animal models of ESCC. Collectively, we provide a spatially resolved landscape of the prometastatic tumor microenvironment in ESCC and highlight the biological and clinical importance of GPR116+ pericytes, proposing potential innovative therapeutic strategies for metastatic cancers. This study provides a single-cell and spatial atlas of the prometastatic tumor microenvironment in esophageal squamous cell carcinoma and characterizes the immunosuppressive function of GPR116+ pericytes in cancer metastasis and immune evasion.

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食管鳞状细胞癌的单细胞多组学和空间分析揭示了GPR116+周细胞在肿瘤转移中的免疫抑制作用

肿瘤转移是大多数癌症死亡的原因。然而，肿瘤微环境中的细胞多样性和动态合作如何促进转移仍然知之甚少。本研究利用单细胞多组学（16个样本，117,169个细胞）和空间转录组学（5个样本，195,366个细胞）揭示了食管鳞状细胞癌（ESCC）的细胞和空间结构，并表征了促进肿瘤转移和免疫治疗抵抗的免疫抑制GPR116+周细胞亚群。GPR116+周细胞的富集受PRRX1的转录调节，由周细胞特异性PRRX1敲除小鼠证明。机制上，GPR116+周细胞分泌EGFL6结合癌细胞上的整合素β1，激活NF-κB通路促进转移。血清EGFL6可作为几种肿瘤诊断和预后的无创生物标志物。阻断整合素β1可抑制ESCC动物模型的转移并改善免疫治疗反应。总之，我们提供了ESCC中前转移性肿瘤微环境的空间解析景观，并强调了GPR116+周细胞的生物学和临床重要性，提出了转移性癌症的潜在创新治疗策略。本研究提供了食管鳞状细胞癌转移前肿瘤微环境的单细胞和空间图谱，并表征了GPR116+周细胞在肿瘤转移和免疫逃避中的免疫抑制功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution