Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization
(1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J
Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.
Contributed by Shishir Pant
(1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J
Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info:
(1) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Insti
tute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (2) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. (3) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (4) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (5) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (6) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (7) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (8) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (9) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (10) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (11) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (12) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (13) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (14) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (15) BGI Research, Chongqing, China. Department of Neurology, Hubei Provincial Clinical Research Center for Parkinson's Disease, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China. (16) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (17) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (18) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (19) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (20) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (21) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (22) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (23) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. First Hospital of Shanxi Medical University, Taiyuan, China. Molecular Imaging Precision Medical Collaborative Innovation Center, Shanxi Medical University, Taiyuan, China. (24) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (25) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (26) Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. (27) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (28) BGI Research, Hangzhou, China. (29) BGI Research, Chongqing, China. (30) BGI Research, Chongqing, China. (31) BGI Research, Chongqing, China. (32) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (33) BGI Research, Hangzhou, China. (34) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. BGI, Shenzhen, China. (35) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Stomatology, Zhongshan Hospital Fudan University, Shanghai, China. (36) 3DC STAR Lab, BGI CELL, Shenzhen, China. Prince Fahad bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia. (37) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (38) BGI Research, Chongqing, China. JFL-BGI STOmics Center, Jinfeng Laboratory, Chongqing, China. (39) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (40) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (41) Dunwill Med-Tech, Shanghai, China. (42) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (43) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (44) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (45) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
