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  3. Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma

  • Cancer Cell. 2023 Dec 12:S1535-6108(23)00401-4. doi: 10.1016/j.ccell.2023.11.010.
Yunfan Sun 1,  Pin Wu 2,  Zefan Zhang 3,  Zejian Wang 4,  Kaiqian Zhou 3,  Minfang Song 5,  Yuan Ji 6,  Fenglin Zang 7,  Limu Lou 8,  Keqiang Rao 3,  Pengxiang Wang 3,  Yutong Gu 9,  Jie Gu 10,  Binbin Lu 11,  Limeng Chen 11,  Xiuqi Pan 8,  Xiaojing Zhao 8,  Lihua Peng 12,  Dongbing Liu 12,  Xiaofang Chen 12,  Kui Wu 12,  Penghui Lin 12,  Liang Wu 13,  Yulin Su 8,  Min Du 14,  Yingyong Hou 6,  Xinrong Yang 3,  Shuangjian Qiu 3,  Yinghong Shi 3,  Huichuan Sun 3,  Jian Zhou 3,  Xingxu Huang 5,  David H Peng 15,  Liye Zhang 16,  Jia Fan 17
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. Electronic address: [email protected].
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Shenzhen 518083, China.
  • 3 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Research Center for Intelligent Computing Platforms, Zhejiang Lab, Hangzhou, Zhejiang 311121, China.
  • 6 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 7 Department of Pathology, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
  • 9 Department of Orthopaedic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China.
  • 10 Department of Thoracic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China.
  • 11 Dunwill Med-Tech, Shanghai 200032, China.
  • 12 BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China.
  • 13 BGI Research, Shenzhen 518083, China.
  • 14 Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200032, China.
  • 15 Dunwill Med-Tech, Shanghai 200032, China. Electronic address: [email protected].
  • 16 School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: [email protected].
  • 17 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. Electronic address: [email protected].
PMID: 38101410 DOI: 10.1016/j.ccell.2023.11.010
Abstract

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

Keywords

NKG2A checkpoint; Wnt; cancer evolution; chromosome instability; hepatocellular carcinoma; intratumor heterogeneity; metastasis; negative selection; polyclonal metastasis; tumor microenvironment.

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