title: Niche appropriation by Drosophila intestinal stem cell tumours.
abstract: Mutations that inhibit differentiation in stem cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila intestinal stem cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress-dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the stem cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective stem cells may be a common mechanism of early tumorigenesis.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North Seattle, Washington 98109, USA.|German Cancer Research Center (DKFZ)-Center for Molecular Biology, University of Heidelberg Alliance, Im Neuenheimer Feld 282 69120 Heidelberg, Germany.
authors.forename: Parthive H
authors.initials: PH
authors.lastname: Patel
authors.affiliation: German Cancer Research Center (DKFZ)-Center for Molecular Biology, University of Heidelberg Alliance, Im Neuenheimer Feld 282 69120 Heidelberg, Germany.
authors.forename: Devanjali
authors.initials: D
authors.lastname: Dutta
authors.affiliation: German Cancer Research Center (DKFZ)-Center for Molecular Biology, University of Heidelberg Alliance, Im Neuenheimer Feld 282 69120 Heidelberg, Germany.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D002448:Cell Adhesion; D049109:Cell Proliferation; D016207:Cytokines / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D020895:Enterocytes / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D009132:Muscles / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000502:physiology*; D018010:Receptors, Invertebrate Peptide / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D016207:Cytokines; D029721:Drosophila Proteins; C497759:N protein, Drosophila; D018010:Receptors, Invertebrate Peptide; D051880:Receptors, Notch; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors