A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.
Bogdan-Tiberius Preca, Karolina Bajdak, Kerstin Mock, Waltraut Lehmann, Vignesh Sundararajan, Peter Bronsert, Alexandra Matzge-Ogi, Véronique Orian-Rousseau, Simone Brabletz, Thomas Brabletz, Jochen Maurer, Marc P Stemmler
Author Information
Bogdan-Tiberius Preca: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Karolina Bajdak: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Kerstin Mock: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Waltraut Lehmann: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Vignesh Sundararajan: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Peter Bronsert: German Cancer Consortium (DKTK), Heidelberg, Germany.
Alexandra Matzge-Ogi: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany.
Véronique Orian-Rousseau: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany.
Simone Brabletz: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Thomas Brabletz: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Jochen Maurer: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Marc P Stemmler: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
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.
