Abstract 2892: Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling

Abstract

Abstract Increasing evidence suggests that tumor cell plasticity promotes metastasis and tumor recurrence, resulting in cancer patient mortality. While it is clear that the tumor microenvironment (TME) contributes to tumor cell plasticity, the specific TME factors that actively generate tumor cell plasticity are largely unknown. Here, we identify TME cytokines that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem-cell (CSC) properties. A screen of 27 TME cytokines identified multiple Interleukin-6 family members as inducers of mesenchymal/CSC properties, with Oncostatin M (OSM) being the most potent. Importantly, OSM induced plasticity was mediated by STAT3, but also dependent on TGF-β signaling and downstream SMAD3. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented the OSM-induced mesenchymal/CSC properties. OSM-activated STAT3 binds to SMAD3 and promotes SMAD3 nuclear localization and binding to the SNAIL promoter, increasing transcription of the SNAIL gene. The epithelial-mesenchymal transition induced by the STAT3/SMAD3 axis results in a highly invasive and metastatic phenotype and the emergence of CSC properties, including therapeutic resistance. Importantly, maintenance of the OSM-induced mesenchymal/CSC state requires sustained exposure to the cytokine, as removal of OSM results in a marked phenotypic reversion. A high-throughput screen for small molecule inhibitors of the OSM-induced mesenchymal/CSC phenotype has been performed and are currently being confirmed. We propose that, targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity associated with metastasis and tumor recurrence. Citation Format: Benjamin L. Bryson, Damian J. Junk, Jacob Smigiel, Neetha Parameswaran, Mary R. Doherty, Courtney A. Bartel, Mark Jackson. Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2017-2892