TY  - JOUR
AU  - Lim, Bryce
AU  - Kamal, Aryan
AU  - Gomez Ramos, Borja
AU  - Adrian Segarra, Juan
AU  - Ibarra, Ignacio L
AU  - Dignas, Lennart
AU  - Kindinger, Tim
AU  - Volz, Kai
AU  - Rahbari, Mohammad
AU  - Rahbari, Nuh
AU  - Poisel, Eric
AU  - Kafetzopoulou, Kanela
AU  - Böse, Lio
AU  - Breinig, Marco
AU  - Heide, Danijela
AU  - Gallage, Suchira Upeksha
AU  - Barragan Avila, Jose Efren
AU  - Wiethoff, Hendrik
AU  - Berest, Ivan
AU  - Schnabellehner, Sarah
AU  - Schneider, Martin
AU  - Becker, Jonas
AU  - Helm, Dominic
AU  - Grimm, Dirk
AU  - Mäkinen, Taija
AU  - Tschaharganeh, Darjus F
AU  - Heikenwalder, Mathias
AU  - Zaugg, Judith B
AU  - Mall, Moritz
TI  - Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis.
JO  - Nature genetics
VL  - 57
IS  - 3
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2025-00370
SP  - 668-679
PY  - 2025
N1  - DKFZ-ZMBH Alliance /#EA:A340#LA:A340# / 2025 Mar;57(3):668-679
AB  - Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether 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 alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
LB  - PUB:(DE-HGF)16
C6  - pmid:39948437
DO  - DOI:10.1038/s41588-025-02081-w
UR  - https://inrepo02.dkfz.de/record/298936
ER  -