To be or not to be (a biliary cancer): RAS (signalling) is the question

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent type of primary liver cancer, presents with a highly dismal prognosis, and its incidence is on the rise compared with most cancers.1 iCCA features histological traits of the biliary tract including expression of biliary epithelial cell markers such as SRY-box transcription factor 9 and cytokeratin 19. Based on the histological appearance, iCCA has been considered to arise from mature cholangiocytes. Indeed, epidemiological studies associate iCCA with pathological conditions involving the biliary compartment such as primary sclerosing cholangitis and liver fluke infection.1 Nonetheless, the presence of mixed hepatocellular carcinoma (HCC)/iCCA tumours, along with the association of iCCA with conditions affecting the hepatocellular compartment such as hepatitis B and C, and cirrhosis, points to the potential involvement of additional cell types, such as hepatocytes, in the origin of iCCA.1 Pioneering lineage tracing studies reported the development of murine iCCA derived from hepatocytes on treatment with the carcinogenic agent thioacetamide or by hydrodynamic tail vein injection (HTVI) delivery of iCCA-related oncogene Notch (ie, Notch intracellular domain), into hepatocytes of adult mice using the Sleeping Beauty transposon-transposase system.2 3 Hepatocyte to biliary cell (H-BC) transdifferentiation was further supported by subsequent studies using HTVI to overexpress oncogenes and/or deplete tumour suppressor genes (TSGs) and, more recently, by the use of adeno-associated virus with preferential tropism to hepatocytes.4–8 While these studies started to highlight that different liver injuries and pro-oncogenic insults foster H-BC transdifferentiation, the molecular understanding of how this process is regulated is far from being complete. This issue of Gut features a study …