A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models

Zhong, Zheng, Harmston, Nathan, Wood, Kris C., Madan, Babita and Virshup, M. 2022. A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models. Journal of Clinical Investigation 132 (12) , e156305. 10.1172/JCI156305

PDF - Published Version Available under License Creative Commons Attribution. Download (49MB)

Abstract

Wnt signaling regulates the balance between stemness and differentiation in multiple tissues and in cancer. RNF43-mutant pancreatic cancers are dependent on Wnt production, and pharmacologic blockade of the pathway, e.g., by PORCN inhibitors, leads to tumor differentiation. However, primary resistance to these inhibitors has been observed. To elucidate potential mechanisms, we performed in vivo CRISPR screens in PORCN inhibitor–sensitive RNF43-mutant pancreatic cancer xenografts. As expected, genes in the Wnt pathway whose loss conferred drug resistance were identified, including APC, AXIN1, and CTNNBIP1. Unexpectedly, the screen also identified the histone acetyltransferase EP300 (p300), but not its paralog, CREBBP (CBP). We found that EP300 is silenced due to genetic alterations in all the existing RNF43-mutant pancreatic cancer cell lines that are resistant to PORCN inhibitors. Mechanistically, loss of EP300 directly downregulated GATA6 expression, thereby silencing the GATA6-regulated differentiation program and leading to a phenotypic transition from the classical subtype to the dedifferentiated basal-like/squamous subtype of pancreatic cancer. EP300 mutation and loss of GATA6 function bypassed the antidifferentiation activity of Wnt signaling, rendering these cancer cells resistant to Wnt inhibition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	30 August 2023
Date of Acceptance:	4 May 2022
Last Modified:	01 Sep 2023 05:50
URI:	https://orca.cardiff.ac.uk/id/eprint/161890

Actions (repository staff only)

Edit Item