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@ARTICLE{Rao:305608,
author = {S. V. Rao and L. Young and D. Cheeseman and S. Flynn and N.
Krebs and D.-L. Couturier and S. Mack and R. Brais and J.
Temple and A. Smith and E. Papachristou and C. Pelicano and
C. S. R. Chilamakuri and K. Herka and H. Baba and L.
Farah$^*$ and P. F. Cheung$^*$ and J. Siveke$^*$ and S.
Guerrier and L. Insolia and M. Gill and E. Archer Goode and
S. Kupczak and Y. Cheng and G. Borsari and D. Jodrell and C.
D'Santos and A. Russell and B. T. Grünwald and E. Serrao
and I. Chernukhin and J. S. Carroll},
title = {{T}ranscription factor switching drives subtype-specific
pancreatic cancer.},
journal = {Nature genetics},
volume = {nn},
issn = {1061-4036},
address = {London},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {DKFZ-2025-02258},
pages = {nn},
year = {2025},
note = {epub},
abstract = {Emerging evidence suggests that lineage-specifying
transcription factors control the progression of pancreatic
ductal adenocarcinoma (PDAC). We have discovered a
transcription factor switching mechanism involving the
poorly characterized orphan nuclear receptor HNF4G and the
putative pioneer factor FOXA1, which drives PDAC
progression. Using our unbiased protein interactome
discovery approach, we identified HNF4A and HNF4G as
reproducible, FOXA1-associated proteins, in both preclinical
models and Whipple surgical samples. In the primary tumor
context, we consistently find that the dominant
transcription factor is HNF4G, where it functions as the
driver. A molecular switch occurs in advanced disease,
whereby HNF4G expression or activity decreases, unmasking
FOXA1's transcriptional potential. Derepressed FOXA1 drives
late-stage disease by orchestrating metastasis-specific
enhancer-promoter loops to regulate the expression of
metastatic genes. Overall survival is influenced by HNF4G
and FOXA1 activity in primary tumor growth and in
metastasis, respectively. We suggest that the existence of
stage-dependent transcription factor activity, triggered by
molecular compartmentalization, mediates the progression of
PDAC.},
cin = {ED01},
ddc = {570},
cid = {I:(DE-He78)ED01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41168397},
doi = {10.1038/s41588-025-02389-7},
url = {https://inrepo02.dkfz.de/record/305608},
}