Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Abstract

Background and Aims: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single‐cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. Approach and Results: Single‐cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single‐cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post–neoadjuvant chemotherapy tumor samples. A single‐cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic‐targeted therapeutic strategy against the CSC‐like HB1–Pro‐like1 subpopulation and its related high‐risk “Pro‐like1” subtype of HB. Conclusions: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single‐cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

EZH2 is a key component of hepatoblastoma tumor cell growth

“…These findings suggest that EZH2 operates in a predominantly noncanonical manner because canonical EZH2 interacts with and requires EED and SUZ12 16 . The stoichiometry of the PRC2 complex requires correspondingly elevated protein levels of EED and SUZ12 53,54 . Noncanonical mechanisms of EZH2 function as they relate to β‐catenin function have been reported.…”

“…16 The stoichiometry of the PRC2 complex requires correspondingly elevated protein levels of EED and SUZ12. 53,54 Noncanonical mechanisms of EZH2 function as they relate to β-catenin function have been reported. A recent study demonstrated that EZH2…”

“…Using scRNA-seq, other groups have also postulated that HB consists of multiple genomically unique cell populations. 10,[51][52][53] Therefore, isolation and characterization of these cell subclusters will become important to understand tumor development, evolution, self-renewal, and metastasis, to target the HB patients most in need of novel therapies. Indeed, in a clinical study, elevated serum EZH2 may be related to more aggressive disease.…”

“…Although this finding may be explained by clinical sampling variability, it may also be consistent with our previous finding that EZH2 expression is mostly limited to the Tr2 cell subcluster. Using scRNA‐seq, other groups have also postulated that HB consists of multiple genomically unique cell populations 10,51–53 . Therefore, isolation and characterization of these cell subclusters will become important to understand tumor development, evolution, self‐renewal, and metastasis, to target the HB patients most in need of novel therapies.…”

Machine learning and single cell RNA sequencing analysis identifies regeneration-related hepatocytes and highlights a Birc5-related model for identifying cell proliferative ability

“…During post-hepatectomy acute liver injury, newborn hepatocytes arise from the self-replication of residual hepatocytes, highlighting the proliferation and division of mature hepatocytes as the fastest and most effective method of liver regeneration (Michalopoulos and Bhushan 2021). Notably, Single-cell RNA sequencing (scRNA-seq) is a powerful approach to explore cell structure and characterize cell identity (Huang et al 2022), especially identifying different cell populations and explaining the heterogeneity or correlation between cells. In conclusion, liver regeneration is a critical topic of interest in clinical scenarios and cutting-edge cellular therapies for liver disease.…”