Therapeutic potential of SOX9 dysruption in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) represents a challenging subtype of primary liver cancer with limited treatment options and a poor prognosis. Recently, we and others have highlighted the context-dependent roles of the biliary-specific transcription factor SOX9 in the pathogenesis of liver cancers using various applications in strains, to achieve elimination for exon 2 and 3 of the gene locus as a preventive manner. Here, we reveal the contrasting responses of developmental elimination using ( LKO) versus -based tumor specific acute CKO in SB-HDTVI-based and cHCC-CCA formation. LKO specifically abrogates the CCA region while robustly stimulating the proliferation of remaining poorly differentiated HCC pertaining liver progenitor cell characteristics, whereas CKO potently prevents and cHCC-CCA development irrespective of fate of tumor cells compared to respective controls. Additionally, we find that , but not , tumor formation is partially dependent on the cascade. Pathologically, SOX9 is indispensable for -mediated HC-to-BEC/CCA reprogramming but required for the maintenance of CCA nodules. Lastly, therapeutic elimination of using the strain combined with an inducible -based iKO significantly reduces cHCC-CCA tumor burden, similar to CKO. Thus, we contrast the outcomes of acute deletion with developmental knockout models, emphasizing the importance of considering adaptation mechanisms in therapeutic strategies. This necessitates the careful consideration of genetic liver cancer studies using developmental Cre and somatic mutant lines, particularly for genes involved in hepatic commitment during development. Our findings suggest that SOX9 elimination may hold promise as a therapeutic approach for cHCC-CCA and underscore the need for further investigation to translate these preclinical insights into clinical applications.