Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling.

// Yvonne Moller 1 , Markus Morkel 2 , Jens Schmid 3 , Sven Beyes 1, 8 , Janina Hendrick 1 , Michaela Strotbek 1 , Pamela Riemer 2, 4 , Simone Schmid 1 , Lisa C. Schmitt 1 , Roland Kontermann 1, 5 , Thomas Murdter 3 , Matthias Schwab 3, 6, 7 , Christine Sers 2, 4 , Monilola A. Olayioye 1, 5 1 Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany 2 Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany 3 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tubingen, Stuttgart, Germany 4 DKTK, German Cancer Consortium, Partner site Charite, Berlin, Germany 5 Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany 6 Department of Clinical Pharmacology, University Hospital, Tubingen, Germany 7 Department of Biochemistry and Pharmacy, University of Tubingen, Tubingen, Germany 8 Current address: Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany Correspondence to: Monilola A. Olayioye, email: monilola.olayioye@izi.uni-stuttgart.de Keywords: oncogenic Ras, ErbB3/HER3, 3D culture, intestinal organoids, apical-basolateral polarity Received: January 31, 2016      Accepted: July 09, 2016      Published: July 18, 2016 ABSTRACT 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-Ras G12V -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.