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 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. [Display omitted] • Multi-regional and multi-omic profiles of paired primary and metastatic HCC tumors • Polyclonal, early dissemination and APM defects result in high ITH in metastases • Wnt-wt subclones show stronger selection for metastasis than Wnt-mut counterparts • Focal and arm-level SCNA deletion events are genomic drivers of HCC metastasis Sun et al. characterize multi-regional and multi-omics (genomics, transcriptomics, scRNA-seq, spatial transcriptomics, and IHC) profiles for paired primary and metastatic hepatocellular carcinoma from 182 patients. They reveal high intratumor heterogeneity in metastatic HCCs, complex evolutionary trajectories, subclonal selection, and crucial roles of tumor microenvironment (cancer-associated fibroblast and B cells) during metastasis. [ABSTRACT FROM AUTHOR]