Roles of microbiota-mediated hepatocarcinogenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The gut microbiota plays a crucial role in modulating: 1) conditions predisposing to cancer, 2) cancer initiation, progression, and metastasis, and 3) response to therapy. Our previous studies revealed a common Asian molecular subtype shared between HCC and iCCA, associated with obesity and inflammatory responses, such as increased bile acid metabolism and gamma delta T-cell infiltration. These findings lead us to hypothesize that ethnicity-related differences in the gut microbiome may contribute to this shared subtype in Asian patients with HCC and iCCA. The liver, considered an immune organ, receives its primary blood supply from the portal vein, which often carries potential pathogens. HCC and iCCA frequently develop in individuals with chronic liver diseases caused by sustained liver damage, inflammation, and regeneration. These conditions are often associated with gut dysbiosis, compromised mucosal integrity, and increased permeability. The bacterial microbiome, along with microbial molecular patterns and bacterial metabolites, plays a key role in liver disease progression and liver cancer development. The role of inflammation in liver disease and cancer is well established, with recent advances highlighting how gut and liver microbiota regulate liver carcinogenesis and metastasis. As a result, the intestinal-microbiota-liver axis is increasingly recognized as a promising target for preventing and treating liver diseases, including HCC and iCCA. Accordingly, we are investigating liver cancer-associated bacteria in clinical samples. We aim to: 1) identify tumor-associated microbiota in HCC and iCCA; 2) investigate the molecular mechanisms through which microbial antigens influence cancer development; and 3) analyze the correlation between tumor-associated microbiota, tumor transcriptome, molecular subtypes, prognosis, and immune microenvironment in HCC and iCCA. By integrating microbiome data with tumor biology, together with the immunopeptidomic data described below, we aim to gain a comprehensive understanding of how microbiota influences liver cancer development. This includes correlating microbial signatures with tumor transcriptomic profiles to understand gene expression changes driven by microbes and examining their impact on patient prognosis and the immune microenvironment.