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000305608 1001_ $$aRao, Shalini V$$b0
000305608 245__ $$aTranscription factor switching drives subtype-specific pancreatic cancer.
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000305608 520__ $$aEmerging 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.
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000305608 7001_ $$aYoung, Lisa$$b1
000305608 7001_ $$aCheeseman, Danya$$b2
000305608 7001_ $$aFlynn, Sean$$b3
000305608 7001_ $$aKrebs, Niklas$$b4
000305608 7001_ $$00000-0001-5774-5036$$aCouturier, Dominique-Laurent$$b5
000305608 7001_ $$aMack, Stephanie$$b6
000305608 7001_ $$aBrais, Rebecca$$b7
000305608 7001_ $$aTemple, Jill$$b8
000305608 7001_ $$aSmith, Amy$$b9
000305608 7001_ $$00000-0002-5835-2055$$aPapachristou, Evangelia$$b10
000305608 7001_ $$00000-0002-7039-2922$$aPelicano, Catarina$$b11
000305608 7001_ $$aChilamakuri, Chandra Sekhar Reddy$$b12
000305608 7001_ $$aHerka, Krzysztof$$b13
000305608 7001_ $$aBaba, Hideo$$b14
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000305608 7001_ $$0P:(DE-HGF)0$$aCheung, Phyllis F$$b16
000305608 7001_ $$0P:(DE-He78)026e0a55b968f360a3c349689ce8a99c$$aSiveke, Jens$$b17$$udkfz
000305608 7001_ $$aGuerrier, Stéphane$$b18
000305608 7001_ $$00000-0003-4169-5446$$aInsolia, Luca$$b19
000305608 7001_ $$aGill, Michael$$b20
000305608 7001_ $$aArcher Goode, Emily$$b21
000305608 7001_ $$aKupczak, Steven$$b22
000305608 7001_ $$aCheng, Yi$$b23
000305608 7001_ $$00000-0002-0584-5737$$aBorsari, Giacomo$$b24
000305608 7001_ $$00000-0001-9360-1670$$aJodrell, Duncan$$b25
000305608 7001_ $$aD'Santos, Clive$$b26
000305608 7001_ $$aRussell, Alasdair$$b27
000305608 7001_ $$aGrünwald, Barbara T$$b28
000305608 7001_ $$aSerrao, Eva$$b29
000305608 7001_ $$aChernukhin, Igor$$b30
000305608 7001_ $$00000-0003-3643-0080$$aCarroll, Jason S$$b31
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