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<p>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<sup>+</sup> pericyte subset promoting tumor metastasis and immunotherapy resistance. GPR116<sup>+</sup> pericyte enrichment is transcriptionally regulated by PRRX1, evidenced by pericyte-specific <i>Prrx1</i> knockout mice. Mechanistically, GPR116<sup>+</sup> 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<sup>+</sup> pericytes, proposing potential innovative therapeutic strategies for metastatic cancers.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月10日

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  • 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

摘要

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.