Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization
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 Phgdh high 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. Cx3cr1 high 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.
Authors
- Guibo Li (ORCID: https://orcid.org/0000-0002-6141-4931)
- Yun‐Fan Sun (ORCID: https://orcid.org/0000-0001-9790-2761)
- Miguel A. Esteban (ORCID: https://orcid.org/0000-0002-1426-6809)
- Zefan Zhang (ORCID: https://orcid.org/0000-0001-5627-050X)
- Junbing Chen (ORCID: https://orcid.org/0000-0002-5741-1332)
- Hui‐Chuan Sun (ORCID: https://orcid.org/0000-0003-3761-7058)
- Shiping Liu (ORCID: https://orcid.org/0000-0003-0019-619X)
- Zhifang Wu (ORCID: https://orcid.org/0000-0003-0376-982X)
- Yinqi Bai (ORCID: https://orcid.org/0000-0003-1017-5712)
- Yu Zhong (ORCID: https://orcid.org/0000-0001-6902-2732)
- Jiyan Wang (ORCID: https://orcid.org/0000-0002-0518-8626)
- Wei Guo (ORCID: https://orcid.org/0000-0002-9924-638X)
- Shuang Yang (ORCID: https://orcid.org/0000-0002-8244-3002)
- Waidong Huang (ORCID: https://orcid.org/0009-0001-6125-0148)
- Keqiang Rao
- Yong Cang (ORCID: https://orcid.org/0000-0002-1148-7008)
- Xin Jin (ORCID: https://orcid.org/0000-0001-7554-4975)
- Lihua Peng (ORCID: https://orcid.org/0000-0001-8358-5179)
- Ying‐Hong Shi (ORCID: https://orcid.org/0000-0002-1833-8988)
- Ao Chen (ORCID: https://orcid.org/0000-0002-9699-8340)
- Xi Chen (ORCID: https://orcid.org/0000-0002-7995-6202)
- Yuhang Wang (ORCID: https://orcid.org/0000-0001-6804-0445)
- Xun Xu (ORCID: https://orcid.org/0000-0002-5338-5173)
- Jia Fan (ORCID: https://orcid.org/0000-0001-5158-629X)
- Jian Zhou (ORCID: https://orcid.org/0000-0002-2118-1117)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-3463-9350)
- Shang Liu (ORCID: https://orcid.org/0000-0002-3403-8651)
- Liang Wu (ORCID: https://orcid.org/0000-0001-6259-261X)
- Tian Ru
- Chunqing Wang (ORCID: https://orcid.org/0000-0002-2811-7230)
- Zifei Wang (ORCID: https://orcid.org/0000-0001-6835-695X)
- Miaomiao Jiang (ORCID: https://orcid.org/0000-0002-8473-8955)
- Min Xie (ORCID: https://orcid.org/0000-0002-5652-5039)
- Muzi Cao
- Yang Liu (ORCID: https://orcid.org/0000-0001-8552-0096)
- David H. Peng
- Jian Wang
- Yuanhang Zhang (ORCID: https://orcid.org/0009-0003-5370-9582)
- Yue Wang
- Feng Xi
- Xiaohu Huang (ORCID: https://orcid.org/0009-0008-6721-5264)
- Shuangjian Qiu
- Xiaoying Gu
- Xuanxuan Zou
- Jie Gu
- Shuang Yang
- Jian Wang
- Yue Wang
- Shiping Liu (ORCID: https://orcid.org/0000-0003-0019-619X)
- Xi Chen
- Shang Liu
- Chunqing Wang (ORCID: https://orcid.org/0009-0002-2330-7091)
- Xuanxuan Zou
- Jie Gu
Institutions
- BGI Group (China) (CN)
- Hubei University of Medicine (CN)
- Sun Yat-sen University (CN)
- Shanxi Medical University (CN)
- Fudan University (CN)
- Ruijin Hospital (CN)
- ShanghaiTech University (CN)
- Fahd bin Sultan University (SA)
- First Hospital of Shanxi Medical University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Ministry of Education (ET)
- Xiang Yang No.1 People's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- BGI Research (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Science
- Published
- 2026-07-30
- DOI
- https://doi.org/10.1126/science.adz7928
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Chongqing Postdoctoral Science Foundation
- National Natural Science Foundation of China
- Basic and Applied Basic Research Foundation of Guangdong Province