Journal Article

DKFZ-2025-00370

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis.

Lim, B. (First author)DKFZ* ; Kamal, A. ; Gomez Ramos, B.DKFZ* ; Adrian Segarra, J.DKFZ* ; Ibarra, I. L. ; Dignas, L.DKFZ* ; Kindinger, T.DKFZ* ; Volz, K.DKFZ* ; Rahbari, M.DKFZ* ; Rahbari, N. ; Poisel, E.DKFZ* ; Kafetzopoulou, K.DKFZ* ; Böse, L.DKFZ* ; Breinig, M.DKFZ* ; Heide, D.DKFZ* ; Gallage, S. U.DKFZ* ; Barragan Avila, J. E.DKFZ* ; Wiethoff, H. ; Berest, I. ; Schnabellehner, S. ; Schneider, M.DKFZ* ; Becker, J.DKFZ* ; Helm, D.DKFZ* ; Grimm, D. ; Mäkinen, T. ; Tschaharganeh, D. F.DKFZ* ; Heikenwalder, M.DKFZ* ; Zaugg, J. B. ; Mall, M. (Last author)DKFZ*

2025
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-025-02081-w

Abstract: 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.

Note: DKFZ-ZMBH Alliance /#EA:A340#LA:A340# / 2025 Mar;57(3):668-679

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Contributing Institute(s):

1. A340 NWG Engeneering von Zellidentitäten und Krankheitsmodellen (A340)
2. NWG Cell Plasticity and Epigenetic Remodeling (F190)
3. Chronische Entzündung und Krebs (D440)
4. Proteomics (W120)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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