Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization

• 成果类型: Article
• 署名作者: Sun, Yunfan; Zhong, Yu; Liu, Shang; Zhang, Zefan; Wang, Chunqing; Liu, Yang; Chen, Junbing; Guo, Wei; Gu, Xiaoying; Rao, Keqiang; Wang, Zifei; Cao, Muzi; Wang, Yue; Huang, Waidong; Zou, Xuanxuan; Chen, Xi; Qiu, Shuangjian; Shi, Yinhong; Sun, Huichuan; Huang, Xiaohu; Wang, Yuhang; Wang, Jiyan; Wu, Zhifang; Tian, Ru; Zhang, Yuanhang; Gu, Jie; Jiang, Miaomiao; Bai, Yinqi; Li, Guibo; Xie, Min; Xi, Feng; Peng, Lihua; Liu, Shiping; Yang, Shuang; Zhang, Yu; Esteban, Miguel A.; Jin, Xin; Chen, Ao; Wang, Jian; Cang, Yong; Peng, David H.; Xu, Xun; Zhou, Jian; Wu, Liang; Fan, Jia
• 署名单位: Fudan University; Fudan University; Beijing Genomics Institute (BGI); Chongqing Medical University; Shanghai Jiao Tong University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; ShanghaiTech University; Fudan University; Shanxi Medical University; Shanxi Medical University; Shanxi Medical University; Fudan University; Beijing Genomics Institute (BGI); Fudan University; Fudan University; University of Tabuk; Jinfeng Laboratory
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adz7928
• 发表日期: 2026-07-30
• 页码: eadz7928
• 关键词: gene-expression; read alignment; cancer; atlas

摘要

The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.