title: Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.
abstract: Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: John
authors.initials: J
authors.lastname: Vaughen
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: igaki@lif.kyoto-u.ac.jp.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Igaki
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology*; D025461:Feedback, Physiological; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D000097905:Roundabout Proteins
chemical_list: D015820:Cadherins; D029721:Drosophila Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; C421243:Robo2 protein, Drosophila; D000097905:Roundabout Proteins; C066819:sli protein, Drosophila
keywords: Drosophila; Ena/VASP; JNK; Slit-Robo; cell competition; cell extrusion; scrib; tumor suppression