Deciphering the Molecular Mechanisms Underlying Cholangiocarcinoma Development

Cholangiocarcinoma (CCA) presents a significant clinical challenge with increasing incidence and mortality in the US. Annually, around 8,000 new CCA cases were diagnosed, with a dismal 5-year survival rate of less than 10%. Extremely heterogeneous molecular signatures and resistance to immune checkpoint inhibitors (ICIs) and targeted therapies render surgical resection the most reliable treatment, but early detection is extremely challenging, limiting this option to a small group of patients. There is an urgent need for biomarkers for early detection and prevention strategies during premalignant stages. Cholestatic diseases (CD), including primary sclerosing cholangitis (PSC), significantly increase the risk of CCA, with over 20% of PSC patients developing CCA within one to two decades. While treatments such as UDCA and Farnesoid X-Activated Receptor (FXR) agonists reduce cholestatic injuries, their long-term effects on CD-to-CCA pathology remain controversial and underexplored. Additionally, the roles of FXR and Constitutive Androstane Receptor (CAR) in hepatic tumorigenesis and the regulation of the tumor microenvironment (TME) in CD-CCA contexts are poorly understood. Our preliminary data indicate that FXR activation promotes the malignant transformation of hepatocytes (HCs) into CCA in CD settings, an effect diminished by CAR activation. We hypothesize that FXR activation in CD settings promotes CCA formation by SHP-dependent repression of CAR-mediated transcriptional networks, affecting both tumor-intrinsic transformation and extrinsic immune clearance. In aim 1, we will Investigate the intertwined roles of FXR and/or CAR in HC-CCA transformation within a CD context. We will employ pharmacogenetic tools including innovative inducible gene modulation systems to achieve conditional and inducible deletion of targets in advanced CCA. In aim 2, we will comprehensively elucidate how FXR/CAR regulates immune surveillance, reducing CCA in a CD context. We will determine functional contributors in CCA clearance and assess the ICI combination effect on CD-CCA pathology. In Aim 3, we will delineate molecular mechanisms by which FXR and/or CAR influence CD-CCA. We will verify FXR-SHP cascade repressing CAR activity regulating CD-CCA and also explore downstream effectors of FXR and CAR in CD-CCA. This research aims to elucidate the roles of FXR and CAR in CCA progression and immune regulation, potentially leading to new biomarkers and therapeutic strategies for early detection and prevention, ultimately improving outcomes for CD-CCA patients.