Abstract 994P
Background
Hepatocellular carcinoma (HCC) is lethal malignancy with second highest worldwide cancer mortality. Cancer stem cell in HCC has been regarded as a major cause of cancer progression. However, molecular and clinical features of stem cell-like HCC contributing aggressive tumor biology and therapeutic resistance remain unclear.
Methods
Transcriptomic signatures was identified by analyzing single-cell transcriptomic data from human fetal and mature hepatocytes and applied to 6 HCC cohorts (total n = 1263). Later, supervised and unsupervised approaches were applied to analyze proteomic data and multiple genomic data such as somatic mutations, mRNA expression, miRNA expression, and copy number alterations were integrated with proteomic data to uncover most correlated genomic alterations with functional products. Clinical significance of subtypes was tested and validated in multiple cohorts of HCC patients.
Results
Integrative analysis of genomic and proteomic data uncovered three subtypes of HCC. Hepatic stem (HS) subtype is characterized by strong stem cell features, vascular invasion, and poor prognosis. Hepatoblast (HB) subtype has moderate stem cell features but high genomic instability and low immune activity. Mature hepatocyte (MH) subtype is characterized by low genomic instability. Importantly, 3 subtypes are highly conserved in two most important pre-clinical models, established HCC cell lines (n = 81) and patient-derived HCC xenograft models (n=168). Most strikingly, 3 subtypes are significantly associated with sorafenib treatment and response to immunotherapy. We further validated subtype-specific sensitivity to sorafenib in HCC cell lines and PDX models. Because these subtypes are highly associated with currently available treatments, our findings may provide the foundation for rationalized marker-based clinical trials.
Conclusions
We identified two distinct stem cell-like subtypes with biomarkers in the tumor tissue. Each subtype has distinct response to immunotherapy and subtype-specific drug response for target agents as well as unique pathway dependencies. Our findings may offer the foundation of biomarker based clinical trials for new therapeutic approaches to refractory HCC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute/NIH.
Disclosure
All authors have declared no conflicts of interest.