Abstract P114: Dissecting the Carcinogenesis Mechanisms of Aristolochic Acid in Cholangiocarcinoma

Abstract

Aristolochic acid (AA) is a potent mutagen found in commonly consumed herbal remedies, causing mutational signature (SBS22) that results in oncogenic transformation of tissues including that of hepatobiliary and genitourinary origins. However, the mechanistic role of AA in tumorigenesis remains unclear, limiting therapeutic strategy development for such cancers. Here, we established the world’s first long-term AA exposed human cell models, which form xenograft tumors in animal models, and confirmed the recapitulation of SBS22a via genome sequencing. Multi-omics integrative analysis unveiled that AA exposure pathogenically reprogrammed the transcriptomic and epigenomic landscapes, to upregulate oncogenic metabolic pathways. Attenuating these pathways using gene silencing and drug inhibitors reduced tumor growth in preclinical models. Overall, our study reveals an actionable AA-specific pathway in CCA and potential therapeutic strategies, providing mechanistic insights and clinical relevance for tumors with AA signatures.