Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Jolly MK, Preca BT, Tripathi SC, Jia D, George JT, Hanash SM, Brabletz T, Stemmler M, Maurer J, Levine H (2018)

Publication Type: Journal article

Publication year: 2018

Journal

APL Bioengineering AIP Publishing LLC

Book Volume: 2

Journal Issue: 3

DOI: 10.1063/1.5024874

Abstract

Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process; rather, cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1-a key transcription factor driving EMT-can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing epithelial splicing regulatory protein 1 (ESRP1), hyaluronic acid synthase 2 (HAS2), and CD44 which maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by experiments showing that knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlate with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.

Authors with CRIS profile

Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung

Involved external institutions

University of Texas Medical Branch (UTMB) US United States (USA) (US) Rice University US United States (USA) (US) Albert-Ludwigs-Universität Freiburg DE Germany (DE)

How to cite

APA:

Jolly, M.K., Preca, B.-T., Tripathi, S.C., Jia, D., George, J.T., Hanash, S.M.,... Levine, H. (2018). Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer. APL Bioengineering, 2(3). https://dx.doi.org/10.1063/1.5024874

MLA:

Jolly, Mohit Kumar, et al. "Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer." APL Bioengineering 2.3 (2018).

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