Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling
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Yvonne Möller1, Markus Morkel2, Jens Schmid3, Sven Beyes1,8, Janina Hendrick1, Michaela Strotbek1, Pamela Riemer2,4, Simone Schmid1, Lisa C. Schmitt1, Roland Kontermann1,5, Thomas Mürdter3, Matthias Schwab3,6,7, Christine Sers2,4, Monilola A. Olayioye1,5
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
2Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany
4DKTK, German Cancer Consortium, Partner site Charité, Berlin, Germany
5Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany
6Department of Clinical Pharmacology, University Hospital, Tübingen, Germany
7Department of Biochemistry and Pharmacy, University of Tübingen, Tübingen, Germany
8Current address: Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany
Monilola A. Olayioye, email: firstname.lastname@example.org
Keywords: oncogenic Ras, ErbB3/HER3, 3D culture, intestinal organoids, apical-basolateral polarity
Received: January 31, 2016 Accepted: July 09, 2016 Published: July 18, 2016
Here we study the effects of inducible oncogenic K-Ras (G12V) expression on the polarized morphogenesis of colonic epithelial cells. We provide evidence that the autocrine production of heregulins, ligands for the ErbB3 receptor tyrosine kinase, is responsible for the hyperproliferation and aberrant 3D morphogenesis upon oncogenic K-Ras expression. This is in line with results obtained in primary intestinal organoid cultures, in which exogenous heregulin is shown to interfere with normal tissue architecture. Importantly, ErbB3 inhibition and heregulin gene silencing rescued K-RasG12V-induced features of cell transformation. Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers, our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression.
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