A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer
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Bogdan-Tiberius Preca1,2,3, Karolina Bajdak1, Kerstin Mock1, Waltraut Lehmann1, Vignesh Sundararajan1, Peter Bronsert2,4,5, Alexandra Matzge-Ogi6,7, Véronique Orian-Rousseau6, Simone Brabletz8, Thomas Brabletz8, Jochen Maurer1,2,3,*, Marc P. Stemmler8,*
1Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
2German Cancer Consortium (DKTK), Heidelberg, Germany
3German Cancer Research Center (DKFZ), Heidelberg, Germany
4Institute for Surgical Pathology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
5Tumorbank Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
6Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany
7Amcure GmbH, Eggenstein-Leopoldshafen, Germany
8Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
*These authors contributed equally to this work
Marc P. Stemmler, email: firstname.lastname@example.org
Keywords: hyaluronic acid synthase 2 (HAS2), epithelial-mesenchymal transition, invasion, metastasis, CD44 signaling
Received: August 15, 2016 Accepted: December 26, 2016 Published: January 09, 2017
Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT.
Marc P. Stemmler
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