Advertisement

ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI156305

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

Zheng Zhong,1 Nathan Harmston,2 Kris C. Wood,3 Babita Madan,1 and David M. Virshup1

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

2Science Division, Yale-NUS College, Singapore, Singapore

3Department of Pharmacology and Cancer Biology, Duke University, Durham, United States of America

Find articles by Zhong, Z. in: JCI | PubMed | Google Scholar |

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

2Science Division, Yale-NUS College, Singapore, Singapore

3Department of Pharmacology and Cancer Biology, Duke University, Durham, United States of America

Find articles by Harmston, N. in: JCI | PubMed | Google Scholar |

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

2Science Division, Yale-NUS College, Singapore, Singapore

3Department of Pharmacology and Cancer Biology, Duke University, Durham, United States of America

Find articles by Wood, K. in: JCI | PubMed | Google Scholar |

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

2Science Division, Yale-NUS College, Singapore, Singapore

3Department of Pharmacology and Cancer Biology, Duke University, Durham, United States of America

Find articles by Madan, B. in: JCI | PubMed | Google Scholar |

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

2Science Division, Yale-NUS College, Singapore, Singapore

3Department of Pharmacology and Cancer Biology, Duke University, Durham, United States of America

Find articles by Virshup, D. in: JCI | PubMed | Google Scholar |

Published May 10, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI156305.
Copyright © 2022, Zhong et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 10, 2022 - Version history
View PDF
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 down-regulated 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 anti-differentiation activity of Wnt signaling, rendering these cancer cells resistant to Wnt inhibition. 

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Table 1

View Supplemental Table 2

View Supplemental Table 4

View Supplemental Table 3

View

Version history
  • Version 1 (May 10, 2022): In-Press Preview
Advertisement
Advertisement