Integrated Multi-Omics Landscape of Liver Metastases

Shuai Yang; Ling Qian; Zhixuan Li; Ye Li; Jian Bai; Bo Zheng; Kun Chen; Xinyao Qiu; Guoxiang Cai; Shan Wang; Haiyan Huang; Jianmin Wu; Yanjing Zhu; Qianwen Zhangyang; Lanyun Feng; Tong Wu; Rui Wu; Airong Yang; Kaiting Wang; Ruiru Wang; Yani Zhang; Yan Zhao; Wenwen Wang; Jinxia Bao; Siyun Shen; Ji Hu; Xuan Wu; Tao Zhou; Zhiqiang Meng; Weiwei Liu; Hongyang Wang; Peng Wang; Lei Chen

doi:10.1053/j.gastro.2022.11.029

Integrated Multi-Omics Landscape of Liver Metastases

Gastroenterology. 2023 Mar;164(3):407-423.e17. doi: 10.1053/j.gastro.2022.11.029. Epub 2022 Nov 26.

Authors

Shuai Yang¹, Ling Qian², Zhixuan Li³, Ye Li², Jian Bai⁴, Bo Zheng³, Kun Chen², Xinyao Qiu⁵, Guoxiang Cai⁶, Shan Wang⁵, Haiyan Huang⁴, Jianmin Wu⁷, Yanjing Zhu³, Qianwen Zhangyang³, Lanyun Feng², Tong Wu³, Rui Wu⁸, Airong Yang⁴, Kaiting Wang⁷, Ruiru Wang⁴, Yani Zhang⁷, Yan Zhao⁷, Wenwen Wang⁹, Jinxia Bao³, Siyun Shen³, Ji Hu³, Xuan Wu¹⁰, Tao Zhou¹¹, Zhiqiang Meng², Weiwei Liu¹², Hongyang Wang¹³, Peng Wang¹⁴, Lei Chen¹⁵

Affiliations

¹ Department of Integrative Oncology, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Integrative Oncology, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
⁴ Berry Oncology Corporation, Beijing, China.
⁵ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
⁸ Department of Biliary Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
⁹ Department of Integrative Oncology, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁰ Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
¹¹ The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Shanghai China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.
¹² Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: huashanvivian@126.com.
¹³ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China. Electronic address: hywangk@vip.sina.com.
¹⁴ Department of Integrative Oncology, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: peng_wang@fudan.edu.cn.
¹⁵ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China. Electronic address: chenlei@smmu.edu.cn.

PMID: 36574521
DOI: 10.1053/j.gastro.2022.11.029

Abstract

Background & aims: Lack of thorough knowledge about the complicated immune microenvironment (IM) within a variety of liver metastases (LMs) leads to inappropriate treatment and unsatisfactory prognosis. We aimed to characterize IM subtypes and investigate potential mechanisms in LMs.

Methods: Mass cytometry was applied to characterize immune landscape of a primary liver cancers and liver metastases cohort. Transcriptomic and whole-exome sequencing were used to explore potential mechanisms across distinct IM subtypes. Single-cell transcriptomic sequencing, multiplex fluorescent immunohistochemistry, cell culture, mouse model, Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used for validation.

Results: Five IM subtypes were revealed in 100 LMs and 50 primary liver cancers. Patients featured terminally exhausted (IM1) or rare T-cell-inflamed (IM2 and IM3) immune characteristics showed worse outcome. Increased intratumor heterogeneity, enriched somatic TP53, KRAS, APC, and PIK3CA mutations and hyperactivated hypoxia signaling accounted for the formation of vicious subtypes. SLC2A1 promoted immune suppression and desert via increasing proportion of Spp1⁺ macrophages and their inhibitory interactions with T cells in liver metastatic lesions. Furthermore, SLC2A1 promoted immune escape and LM through inducing regulatory T cells, including regulatory T cells and LAG3⁺CD4⁺ T cells in primary colorectal cancer.

Conclusions: The study provided integrated multi-omics landscape of LM, uncovering potential mechanisms for vicious IM subtypes and confirming the roles of SLC2A1 in regulating tumor microenvironment remodeling in both primary tumor and LM lesions.

Keywords: Liver Metastasis; Multi-Omics; SLC2A1; Tumor Immune Microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Exome Sequencing
Liver Neoplasms* / pathology
Mice
Multiomics*
Mutation
Tumor Microenvironment