ArticleJournal of hepatology2021
Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
Article in Journal of hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 234 papers.
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Who cites it
234 citing papers in PubMed, 365 citations in OpenAlex.
- Integrated single-cell multi-omics characterization reveals lipid-associated macrophage-mediated immunosuppression in neoadjuvant immunotherapy of hepatocellular carcinoma.Nature communications · 2026Trial
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- Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.Neoplasia (New York, N.Y.) · 2026Article
- Explainable machine learning and multimodal single cell analysis link NR4A2 to CD8Journal, genetic engineering & biotechnology · 2026Article
- Decoding the cholangiocarcinoma tumor microenvironment: from single-cell and spatial atlases to translational therapeutic targeting.Journal of translational medicine · 2026Review
- Noninvasive Multi-Omics Radiomic Model Integrating scRNA-seq and Bulk RNA-seq for Hepatocellular Carcinoma Prognosis.Journal of imaging informatics in medicine · 2026Article
- SPINK1-driven cellular heterogeneity and interaction networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.Journal of advanced research · 2026Article
- A reproducible endothelial-state contrast with limited bulk prognostic robustness in hepatocellular carcinoma.Functional & integrative genomics · 2026Article
- Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.Nature communications · 2026Article
- Role of the stromal and immune microenvironment in intrahepatic cholangiocarcinoma.JHEP reports : innovation in hepatology · 2026Review
- Single-Cell Transcriptomic Profiling Reveals Immunometabolic Reprogramming and Cell-Cell Communication in the Tumor Microenvironment of Human Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- Pan-cancer single-cell and spatial transcriptomics analyses delineate response-associated heterogeneity and therapeutic targets of tumor-infiltrating B cells following immune checkpoint blockade.Cancer immunology, immunotherapy : CII · 2026Article
- Multimodal sequencing identifies synergistic mechanisms driving resistance to neoadjuvant nivolumab treatment in hepatocellular carcinoma.Molecular cancer · 2026Article
- Pan-cancer analysis of single-cell profiles with polygenic signals reveals genetic influences on tumor immunity across cancers.Communications biology · 2026Article
- Review
- Integrated analyses reveal a potential role for PFKFB4 in M2 macrophage polarization and hepatocellular carcinoma progression.Cancer cell international · 2026Article
- Targeting NK cell CLEC12B enhances cancer immunotherapy.Nature immunology · 2026Article
- Multiomics and multi-region spatial transcriptome analysis reveal cellular networks and pathways associated with HCC recurrence.JHEP reports : innovation in hepatology · 2026Article
- Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma.Cell reports. Medicine · 2026Article
- Review
174 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsIntratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis.
methodsWe analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA.
resultsUsing transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer.
conclusionsOur study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. LAY SUMMARY: Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.