Hepatocyte-Derived Intrahepatic CCA Requires YAP and SOX9

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

AKT and NOTCH intracellular domain (NICD) targets YAP and SOX9 might be potential targets for therapeutic intervention in intrahepatic CCA subsets, while cholestatic injury or NASH might induce hepatocyte-to-cholangiocyte reprogramming that increases risk of intrahepatic CCA.

It is hypothesized that hepatocytes may be the cell source in a subset of intrahepatic CCAs based on evidence that hepatobiliary injury leads to hepatocyte to cholangiocyte transdifferentiation. The NOTCH and AKT signaling pathways are implicated in malignant transformation of hepatocytes into intrahepatic CCA. In this report, presented at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium, the role of AKT and NOTCH intracellular domain (NICD) targets YAP and SOX9 was assessed in the AKT-NICD–driven preclinical model of hepatocyte-derived intrahepatic CCA, in primary intrahepatic CCA tumors, and in patients with chronic liver diseases, such as nonalcoholic steatohepatitis (NASH) or PSC, which are known risk factors for intrahepatic CCA.

The analysis found high expression levels of pAKT in tumor samples from patients with intrahepatic CCA (N = 108), implicating the AKT pathway in the pathogenesis of intrahepatic CCA. Among patients with NASH and PSC (N = 20), high expression levels of pAKT, SOX9, and YAP were observed in hepatocytes, which was thought to be consistent with independent observations in murine models of cholestatic injury and NASH.

A preclinical mouse model of intrahepatic CCA was developed using co-expression of myristoylated AKT (myrAKT) and NICD in hepatocytes using sleeping beauty transposon/transposase-based hydrodynamic tail vein injection (SB-HTVI). In the AKT-NICD model, deletion of YAP or SOX9 led to decreased intrahepatic CCA burden but not complete abrogation. This was supported by data from SOX9 or YAP single knockout mouse models where remnant AKT/NICD-driven intrahepatic CCA tumors expressing either SOX or YAP were observed. A similar phenotype was also documented in a small subset of human primary CCA tumors (SOX9-positive YAP, 4%; SOX9-negative, YAP-positive, 3.7%), suggesting that deletion of either YAP or SOX9 is not sufficient to completely abrogate intrahepatic CCA development. In the AKT-NICD model, concomitant deletion of YAP and SOX9 was shown to completely inhibit hepatocyte-derived intrahepatic CCA tumor development. Moreover, YAP was shown to be essential for the hepatocyte to cholangiocyte reprogramming, while SOX9 and YAP are essential for intrahepatic CCA proliferation.

These results demonstrate that cholestatic injury or NASH in humans and mice induces hepatocyte-to-cholangiocyte reprogramming that results in elevated risk of intrahepatic CCA development. Moreover, YAP and SOX9 were identified as potential therapeutic targets for intervention in subsets of intrahepatic CCA.

Source: Monga S, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 582.

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