Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)-Multi-Omic and Singulomic Approaches

Overview

Journal Semin Liver Dis

Publisher Thieme

Specialty Gastroenterology

Date 2021 Mar 25

PMID 33764481

Citations 13

Authors

Renumathy Dhanasekaran

Affiliations

Soon will be listed here.

Abstract

Tumor heterogeneity, a key hallmark of hepatocellular carcinomas (HCCs), poses a significant challenge to developing effective therapies or predicting clinical outcomes in HCC. Recent advances in next-generation sequencing-based multi-omic and single cell analysis technologies have enabled us to develop high-resolution atlases of tumors and pull back the curtain on tumor heterogeneity. By combining multiregion targeting sampling strategies with deep sequencing of the genome, transcriptome, epigenome, and proteome, several studies have revealed novel mechanistic insights into tumor initiation and progression in HCC. Advances in multiparametric immune cell profiling have facilitated a deeper dive into the biological complexity of HCC, which is crucial in this era of immunotherapy. Moreover, studies using liquid biopsy have demonstrated their potential to circumvent the need for tissue sampling to investigate heterogeneity. In this review, we discuss how multi-omic and single-cell sequencing technologies have advanced our understanding of tumor heterogeneity in HCC.

Citing Articles

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References

Mahe E, Pugh T, Kamel-Reid S . T cell clonality assessment: past, present and future. J Clin Pathol. 2017; 71(3):195-200. PMC: 5868531. DOI: 10.1136/jclinpath-2017-204761. View

Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y . Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology. 2018; 68(3):1025-1041. DOI: 10.1002/hep.29904. View

Shay J . Role of Telomeres and Telomerase in Aging and Cancer. Cancer Discov. 2016; 6(6):584-93. PMC: 4893918. DOI: 10.1158/2159-8290.CD-16-0062. View

Huang A, Zhao X, Yang X, Li F, Zhou X, Wu K . Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma. J Hepatol. 2017; 67(2):293-301. DOI: 10.1016/j.jhep.2017.03.005. View

Blumer T, Fofana I, Matter M, Wang X, Montazeri H, Calabrese D . Hepatocellular Carcinoma Xenografts Established From Needle Biopsies Preserve the Characteristics of the Originating Tumors. Hepatol Commun. 2019; 3(7):971-986. PMC: 6601318. DOI: 10.1002/hep4.1365. View

Faivre S, Rimassa L, Finn R . Molecular therapies for HCC: Looking outside the box. J Hepatol. 2020; 72(2):342-352. DOI: 10.1016/j.jhep.2019.09.010. View

Hu B, Li H, Guo W, Sun Y, Zhang X, Tang W . Establishment of a hepatocellular carcinoma patient-derived xenograft platform and its application in biomarker identification. Int J Cancer. 2019; 146(6):1606-1617. DOI: 10.1002/ijc.32564. View

Ling S, Hu Z, Yang Z, Yang F, Li Y, Lin P . Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A. 2015; 112(47):E6496-505. PMC: 4664355. DOI: 10.1073/pnas.1519556112. View

Cleary S, Jeck W, Zhao X, Chen K, Selitsky S, Savich G . Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013; 58(5):1693-702. PMC: 3830584. DOI: 10.1002/hep.26540. View

10.

Huang A, Zhang X, Zhou S, Cao Y, Huang X, Fan J . Detecting Circulating Tumor DNA in Hepatocellular Carcinoma Patients Using Droplet Digital PCR Is Feasible and Reflects Intratumoral Heterogeneity. J Cancer. 2016; 7(13):1907-1914. PMC: 5039376. DOI: 10.7150/jca.15823. View

11.

Egeblad M, Nakasone E, Werb Z . Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010; 18(6):884-901. PMC: 2905377. DOI: 10.1016/j.devcel.2010.05.012. View

12.

Bartoschek M, Oskolkov N, Bocci M, Lovrot J, Larsson C, Sommarin M . Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018; 9(1):5150. PMC: 6279758. DOI: 10.1038/s41467-018-07582-3. View

13.

Hou Y, Guo H, Cao C, Li X, Hu B, Zhu P . Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas. Cell Res. 2016; 26(3):304-19. PMC: 4783472. DOI: 10.1038/cr.2016.23. View

14.

Buczak K, Ori A, Kirkpatrick J, Holzer K, Dauch D, Roessler S . Spatial Tissue Proteomics Quantifies Inter- and Intratumor Heterogeneity in Hepatocellular Carcinoma (HCC). Mol Cell Proteomics. 2018; 17(4):810-825. PMC: 5880102. DOI: 10.1074/mcp.RA117.000189. View

15.

Dandri M, Petersen J . Mechanism of Hepatitis B Virus Persistence in Hepatocytes and Its Carcinogenic Potential. Clin Infect Dis. 2016; 62 Suppl 4:S281-8. PMC: 4889895. DOI: 10.1093/cid/ciw023. View

16.

Dhanasekaran R, Nault J, Roberts L, Zucman-Rossi J . Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Gastroenterology. 2018; 156(2):492-509. PMC: 6340723. DOI: 10.1053/j.gastro.2018.11.001. View

17.

Horn S, Figl A, Rachakonda P, Fischer C, Sucker A, Gast A . TERT promoter mutations in familial and sporadic melanoma. Science. 2013; 339(6122):959-61. DOI: 10.1126/science.1230062. View

18.

Hsu H, Chiou T, Chen J, Lee C, Lee P, Peng S . Clonality and clonal evolution of hepatocellular carcinoma with multiple nodules. Hepatology. 1991; 13(5):923-8. View

19.

Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad I . Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012; 44(6):694-8. PMC: 3819251. DOI: 10.1038/ng.2256. View

20.

Spitzer M, Nolan G . Mass Cytometry: Single Cells, Many Features. Cell. 2016; 165(4):780-91. PMC: 4860251. DOI: 10.1016/j.cell.2016.04.019. View