Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

ABSTRACT: Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In line with patient data, PROX1 overexpression in mice blocked initiation and progression of hepatocellular carcinoma and extended survival. Remarkably, Prox1 depletion caused hepatocyte fate loss in vitro, and promoted transdifferentiation of hepatocellular- to cholangio-carcinoma in vivo. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver, Hippocampus

SUBMITTER: Dominic Helm  

LAB HEAD: Dr Moritz Mall

PROVIDER: PXD053043 | Pride | 2024-11-11

REPOSITORIES: Pride