title: Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling.
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-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.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Möller
authors.affiliation: Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schmid
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.|Current address: Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Beyes
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Hendrick
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Strotbek
authors.affiliation: Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|DKTK, German Cancer Consortium, Partner site Charité, Berlin, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Riemer
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Schmid
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Schmitt
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.|Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kontermann
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mürdter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital, Tübingen, Germany.|Department of Biochemistry and Pharmacy, University of Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|DKTK, German Cancer Consortium, Partner site Charité, Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.|Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
authors.forename: Monilola A
authors.initials: MA
authors.lastname: Olayioye
mesh_terms: D019898:Autocrine Communication / Q000502:physiology*; D054337:Cell Dedifferentiation / Q000502:physiology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D009024:Morphogenesis / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D018631:ras Proteins
keywords: 3D culture; ErbB3/HER3; apical-basolateral polarity; intestinal organoids; oncogenic Ras