De novo lumen formation in intrahepatic biliary development and cancer

Abstract

The mammalian liver performs many essential functions, including the secretion of bile into the gut to emulsify lipids. Bile is passed from hepatocytes to the intestine through a complex system of branching tubes: the intrahepatic bile ducts (IHBDs). Aberrant IHBD architecture underlies numerous congenital and acquired diseases in humans, yet how malformations in the ductal tree arise is not well understood, in part because of large gaps in our knowledge of how it normally develops. Furthermore, cancer of the IHBDs, known as intrahepatic cholangiocarcinoma (ICC), represents an increasing disease burden in the United States and is thought to arise in part from the inappropriate reactivation of a developmental program for making bile ducts. Here, I describe the morphogenetic events by which biliary tubes self-organize in the developing liver through an ‘inside-out’ process initiated and driven by the de novo formation of apical lumens within cell-cell boundaries. Through the study of ICC-associated mutations, both in vivo and using a highly tractable 3D cell culture model and quantitative imaging pipeline, I have uncovered underlying aspects of the establishment of apicobasal polarity, and the initiation and expansion of lumens in the biliary system. Importantly, this platform also uncovered fundamental differences in the cellular consequences caused by different ICC alterations in the same gene that could explain newly appreciated clinical and therapeutic heterogeneity. Indeed, this work provides evidence that mutations that primarily impact the organization of a key cellular compartment, namely the interface between the membrane and cortical actomyosin cytoskeleton, can lead to multicellular and tissue-scale defects, and eventually oncogenic transformation. We anticipate that these findings will provide a foundation for the further study of how lumen formation is coordinated with signaling and cell differentiation to generate an elaborate system of ducts in the liver and in other settings, and of the different mechanisms by which ICC mutations can highjack this developmental process.