ZFIN ID: ZDB-PUB-181005-1
STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis
D'Amico, S., Shi, J., Martin, B.L., Crawford, H.C., Petrenko, O., Reich, N.C.
Date: 2018
Source: Genes & Development   32: 1175-1187 (Journal)
Registered Authors: Martin, Benjamin
Keywords: context specificity, epithelial carcinogenesis, inflammation, metastasis
MeSH Terms:
  • Adenocarcinoma/genetics
  • Animals
  • Carcinogenesis
  • Cell Differentiation
  • Epithelial Cells/metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung/cytology
  • Lung Neoplasms/genetics*
  • Lung Neoplasms/metabolism
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms/genetics*
  • Pancreatic Neoplasms/metabolism
  • Phosphoproteins/physiology
  • Proto-Oncogene Proteins p21(ras)/genetics*
  • STAT3 Transcription Factor/chemistry
  • STAT3 Transcription Factor/metabolism*
  • Trans-Activators/physiology
  • Zebrafish
PubMed: 30135074 Full text @ Genes & Dev.
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.