The plasticity of liver epithelial cells during homeostasis, regeneration and tumor formation Sun T1, Pikiolek M1, Orsini V1, Bergling S1, Holwerda S1, Morelli L1, Hoppe PS1, Planas-Paz L1, Yang Y2, Ruffner H1, Bouwmeester T1, Lohmann F1, Terracciano LM3, Roma G1, Cong F2, Tchorz JS1 1Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland 2Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA 3Institute for Pathology, University Hospital Basel, Basel, Switzerland The liver has a remarkable regenerative capacity enabled by the plasticity of its epithelial cell compartments- biliary epithelial cells (BEC) and hepatocytes. Upon injury, activated BEC expand around the portal vein forming a transient luminal epithelium in a process referred to as ductular reaction (DR). Using CRISPR screening in BEC organoids followed by in vivo validation, we identified YAP and mTOR pathways are required for establishing a DR. Using single cell analysis of EPCAM+ BECs within a DR we further revealed novel heterogeneity within the BEC pool (Planas paz & Sun et al., Cell Stem Cell 2019). Hepatocytes can re-enter the cell cycle to repopulate the hepatocyte pool or transdifferentiate into BECs in response to injury. In contrast to organs with high rates of cell turnover that harbor constitutive active tissue stem cell niches, the existence of a specialized tissue stem cell population during liver homeostasis and repair, like AXIN2+ hepatocytes, is controversial. Using lineage tracing, transcriptomics profiling, combined with diverse liver injury models, we assessed the role of WNT/beta-Catenin signaling in controlling hepatocyte proliferation during liver homeostasis and regeneration (Sun et al., Cell Stem Cell 2020). Furthermore, we investigated the function of WNT pathway negative regulators ZNRF3 and RNF43 in restricting hepatocytes proliferation and liver metabolic zonation and revealed how the loss of the two genes lead to hepatocelluler carcinoma.