Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis
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.
Authors
- Ignacio L. Ibarra (ORCID: https://orcid.org/0000-0002-0582-002X)
- Kai Volz
- Lio Böse
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Moritz Mall (ORCID: https://orcid.org/0000-0002-1278-2594)
- Ivan Berest (ORCID: https://orcid.org/0000-0001-7607-9163)
- Dominic Helm (ORCID: https://orcid.org/0000-0001-9321-2069)
- Juan M. Adrian-Segarra (ORCID: https://orcid.org/0000-0002-3712-0554)
- Martin Schneider (ORCID: https://orcid.org/0000-0001-8215-7359)
- Hendrik Wiethoff (ORCID: https://orcid.org/0000-0002-8450-653X)
- Jose Efren Barragan Avila (ORCID: https://orcid.org/0000-0002-9348-909X)
- Judith B. Zaugg (ORCID: https://orcid.org/0000-0001-8324-4040)
- Bryce Lim (ORCID: https://orcid.org/0000-0002-5688-3952)
- Suchira Gallage (ORCID: https://orcid.org/0000-0002-1956-3597)
- Dirk Grimm (ORCID: https://orcid.org/0000-0001-6227-5665)
- Nuh N. Rahbari (ORCID: https://orcid.org/0000-0002-4703-9039)
- Borja Gomez Ramos (ORCID: https://orcid.org/0000-0002-7353-2943)
- Aryan Kamal (ORCID: https://orcid.org/0000-0002-1584-5896)
- Taija Mäkinen (ORCID: https://orcid.org/0000-0002-9338-1257)
- Darjus F. Tschaharganeh (ORCID: https://orcid.org/0000-0002-2369-5138)
- Danijela Heide
- Mohammad Rahbari (ORCID: https://orcid.org/0000-0003-1133-2134)
- Jonas Becker (ORCID: https://orcid.org/0000-0003-3827-3322)
- Marco Breinig (ORCID: https://orcid.org/0009-0000-9740-2986)
- Kanela Kafetzopoulou
- Sarah Schnabellehner (ORCID: https://orcid.org/0000-0003-0558-9339)
- Lennart Dignas
- Eric Poisel
- Tim Kindinger
Institutions
- Uppsala University (SE)
- University of Helsinki (FI)
- German Cancer Research Center (DE)
- University of Basel (CH)
- Universität Ulm (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Hospital of Basel (CH)
- Institute for Sports Medicine (DE)
- Wihuri Research Institute (FI)
- Central Institute of Mental Health (DE)
- German Center for Infection Research (DE)
- German Centre for Cardiovascular Research (DE)
- Department of Biomedicine Basel (CH)
- European Molecular Biology Laboratory (DE)
- DKFZ-ZMBH Alliance (DE)
- European Molecular Biology Laboratory (DE)
- University Medical Centre Mannheim (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1038/s41588-025-02081-w
- Citations
- 11
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 10.30