STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis

Stephen D'Amico; Jiaqi Shi; Benjamin L. Martin; Howard C. Crawford; Oleksi Petrenko; Nancy C. Reich

doi:10.1101/gad.311852.118

STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis

¹Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA;
²Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
³Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA;
⁴Department of Molecular and Integrative Physiology, Ann Arbor, Michigan 48109, USA;
⁵Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA

Corresponding authors: nancy.reich{at}stonybrook.edu, alexei.petrenko2{at}stonybrookmedicine.edu

Abstract

A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. In contrast, persistent STAT3 activation through Tyr705 phosphorylation confers a differentiated epithelial morphology that impacts tumorigenic potential. Our results imply a mechanism in which quantitative differences of STAT3 Tyr705 phosphorylation, as compared with other activation modes, direct discrete outcomes in tumor progression.

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Footnotes

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.311852.118.

Received January 30, 2018.
Accepted July 12, 2018.

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