title: Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia.
abstract: Genomic instability has been observed in essentially all sporadic carcinomas. Here we use Drosophila epithelial cells to address the role of chromosomal instability in cancer development as they have proved useful for elucidating the molecular mechanisms underlying tumorigenic growth. We first show that chromosomal instability leads to an apoptotic response. Interestingly, this response is p53 independent, as opposed to mammalian cells, and depends on the activation of the c-Jun N-terminal kinase (JNK) signaling cascade. When prevented from undergoing programmed cell death (PCD), chromosomal instability induces neoplasic overgrowth. These tumor-like tissues are able to grow extensively and metastasize when transplanted into the abdomen of adult hosts. Detailed analysis of the tumors allows us to identify a delaminating cell population as the critical one in driving tumorigenesis. Cells loose their apical-basal polarity, mislocalize DE-cadherin, and delaminate from the main epithelium. A JNK-dependent transcriptional program is activated specifically in delaminating cells and drives nonautonomous tissue overgrowth, basement membrane degradation, and invasiveness. These findings unravel a general and rapid tumorigenic potential of genomic instability, as opposed to its proposed role as a source of mutability to select specific tumor-prone aneuploid cells, and open unique avenues toward the understanding of the role of genomic instability in human cancer.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Dekanty
authors.forename: Lara
authors.initials: L
authors.lastname: Barrio
authors.forename: Mariana
authors.initials: M
authors.lastname: Muzzopappa
authors.forename: Herbert
authors.initials: H
authors.lastname: Auer
authors.forename: Marco
authors.initials: M
authors.lastname: Milán
mesh_terms: D000782:Aneuploidy; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D016764:Cell Polarity; D043171:Chromosomal Instability; D004330:Drosophila / Q000166:cytology* / Q000235:genetics* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D049750:Genome, Insect; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D015820:Cadherins; D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; C474203:p53 protein, Drosophila; C501889:shg protein, Drosophila