Defining the role of Notch Signalling in Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a dismal prognosis. Few patients present with disease amenable to resection and chemotherapy is not curative. The incidence of ICC is rising worldwide and new therapeutic approaches are urgently required. Notch signalling is critical for the embryological development and regeneration of the biliary tree in the mammalian liver. Dysregulation of Notch is known to drive tumorigenesis in a range of solid and haematological malignancies and the aim of this work was to define its contribution to the pathogenesis of ICC. Transgenic overexpression of Notch1 has been described to result in the formation of biliary lineage tumours in the liver. I have used resected human tissue, a chemically-induced model of ICC in rat and a novel transgenic murine model in which the tumour suppressor p53 is conditionally deleted from biliary epithelia, to demonstrate that endogenous Notch signalling is acting via the Notch3 receptor to drive tumorigenesis. I use multiple independent methods of Notch3 blockade to establish that Notch3 promotes epithelial cell survival and self-renewal in ICC and demonstrate that Notch3 inhibition significantly attenuates tumour growth in vivo. My data suggest that Notch3 promotes activity through the PI3K/AKT cell survival cascade via a mechanism independent of the effector of canonical Notch, RBPJκ. Given the significant toxicity associated with gamma-secretase inhibitors these findings offer a novel and specific target for further investigation and future therapeutic development in ICC.