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

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 betwee...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer cell Vol. 42; no. 1; p. 135
Main Authors:	Sun, Yunfan, Wu, Pin, Zhang, Zefan, Wang, Zejian, Zhou, Kaiqian, Song, Minfang, Ji, Yuan, Zang, Fenglin, Lou, Limu, Rao, Keqiang, Wang, Pengxiang, Gu, Yutong, Gu, Jie, Lu, Binbin, Chen, Limeng, Pan, Xiuqi, Zhao, Xiaojing, Peng, Lihua, Liu, Dongbing, Chen, Xiaofang, Wu, Kui, Lin, Penghui, Wu, Liang, Su, Yulin, Du, Min, Hou, Yingyong, Yang, Xinrong, Qiu, Shuangjian, Shi, Yinghong, Sun, Huichuan, Zhou, Jian, Huang, Xingxu, Peng, David H, Zhang, Liye, Fan, Jia
Format:	Journal Article
Language:	English
Published:	United States 08-01-2024
Subjects:	Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - pathology CD8-Positive T-Lymphocytes - pathology Humans Liver Neoplasms - genetics Liver Neoplasms - pathology Multiomics Mutation Tumor Microenvironment - genetics NKG2A checkpoint intratumor heterogeneity metastasis negative selection polyclonal metastasis cancer evolution tumor microenvironment Wnt hepatocellular carcinoma chromosome instability
Online Access:	Get more information
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	1878-3686
DOI:	10.1016/j.ccell.2023.11.010