PXD053043-1

PXD053043 is an original dataset announced via ProteomeXchange.

Title	Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-11-11
AnnouncementXML	Submission_2024-11-11_00:37:47.068.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dominic Helm
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	ubiquitinylated lysine; phosphorylated residue; sumoylated lysine; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-12 07:30:26	ID requested
⏵ 1	2024-11-11 00:37:47	announced

Dataset with its publication pending

submitter keyword: Cell fate plasticity, gene regulation, transcriptional repression, liver cancer, PROX1

Dr Moritz Mall
contact affiliation	Zellidentitäten und Krankheitsmodellen German Cancer Research Center (DKFZ) Foundation under Public Law Im Neuenheimer Feld 280 69120 Heidelberg
contact email	m.mall@dkfz-heidelberg.de
lab head
Dominic Helm
contact affiliation	Proteomics Core Facility, German Cancer Research Center (DKFZ)
contact email	proteomicscore@dkfz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053043
     1. Label: PRIDE project
     2. Name: Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis