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 pre...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
13 February 2025
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| In: |
Nature genetics
Year: 2025, Jahrgang: 57, Heft: 3, Pages: 668-679 |
| ISSN: | 1546-1718 |
| DOI: | 10.1038/s41588-025-02081-w |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41588-025-02081-w Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41588-025-02081-w 
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| Verfasserangaben: | Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall |
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| 245 | 1 | 0 | |a Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis |c Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall |
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| 520 | |a 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. | ||
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| 650 | 4 | |a Liver cancer | |
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