Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and gl Show more
Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells. Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications. Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The "rich metabolism" subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, wellto-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatorymicroenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32-S37) mutations, and an immune-desert/excluded phenotype. The "glycolysis" subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis. The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity. Show less
Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutation Show more
Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. This study includes 152 resected HCCs; mutations in the Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the Show less