TY  - JOUR
AU  - Rao, Shalini V
AU  - Young, Lisa
AU  - Cheeseman, Danya
AU  - Flynn, Sean
AU  - Krebs, Niklas
AU  - Couturier, Dominique-Laurent
AU  - Mack, Stephanie
AU  - Brais, Rebecca
AU  - Temple, Jill
AU  - Smith, Amy
AU  - Papachristou, Evangelia
AU  - Pelicano, Catarina
AU  - Chilamakuri, Chandra Sekhar Reddy
AU  - Herka, Krzysztof
AU  - Baba, Hideo
AU  - Farah, Luay
AU  - Cheung, Phyllis F
AU  - Siveke, Jens
AU  - Guerrier, Stéphane
AU  - Insolia, Luca
AU  - Gill, Michael
AU  - Archer Goode, Emily
AU  - Kupczak, Steven
AU  - Cheng, Yi
AU  - Borsari, Giacomo
AU  - Jodrell, Duncan
AU  - D'Santos, Clive
AU  - Russell, Alasdair
AU  - Grünwald, Barbara T
AU  - Serrao, Eva
AU  - Chernukhin, Igor
AU  - Carroll, Jason S
TI  - Transcription factor switching drives subtype-specific pancreatic cancer.
JO  - Nature genetics
VL  - nn
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2025-02258
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41168397
DO  - DOI:10.1038/s41588-025-02389-7
UR  - https://inrepo02.dkfz.de/record/305608
ER  -