The lethal giant larvaetumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy

BMC Biology

Research Article

Andrea Pession¹  Annalisa Pession²  Francesca Froldi³  Marcello Ziosi³  Daniela Grifoni³  Paola Bellosta⁴  Dennis Strand⁵  Flavio Garoia⁶  Nicola A Grzeschik⁷  Helena E Richardson⁸ 

[1] Alma Mater Studiorum, Dipartimento di Ginecologia, Ostetricia e Pediatria, Via Massarenti 9, 40138, Bologna, Italy;Alma Mater Studiorum, Dipartimento di Patologia Sperimentale, Via S. Giacomo 14, 40126, Bologna, Italy;Alma Mater Studiorum, Dipartimento di Patologia Sperimentale, Via S. Giacomo 14, 40126, Bologna, Italy;Alma Mater Studiorum, Dipartimento di Biologia Evoluzionistica Sperimentale, Via Selmi 3, 40126, Bologna, Italy;Department of Biology, City College of the City University of New York, Convent Ave at 138th, 10031, New York, NY, USA;First Department of Internal Medicine, Johannes Gutenberg University, 63 Obere Zahlbacherstr, 55131, Mainz, Germany;NGB Genetics s.r.l., University of Ferrara, Via Borsari 46, 44100, Ferrara, Italy;Peter MacCallum Cancer Centre, Research Division, 7 St Andrew's Place, 3002, East Melbourne, Victoria, Australia;Peter MacCallum Cancer Centre, Research Division, 7 St Andrew's Place, 3002, East Melbourne, Victoria, Australia;Department of Anatomy and Cell Biology and Department of Biochemistry and Molecular Biology, University of Melbourne, 3052, Parkville, Victoria, Australia;

关键词: Wing Disc;    Mutant Clone;    Cell Competition;    Wing Pouch;    Cell Death Pattern;   

DOI  :  10.1186/1741-7007-8-33

 received in 2009-11-09, accepted in 2010-04-07,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundNeoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. Precancerous cells are often removed by cell death from normal tissues in the early steps of the tumourigenic process, but the molecules responsible for such a fundamental safeguard process remain in part elusive. With the aim to investigate the molecular crosstalk occurring between precancerous and normal cells in vivo, we took advantage of the clonal analysis methods that are available in Drosophila for studying the phenotypes due to lethal giant larvae (lgl) neoplastic mutation induced in different backgrounds and tissues.ResultsWe observed that lgl mutant cells growing in wild-type imaginal wing discs show poor viability and are eliminated by Jun N-terminal Kinase (JNK)-dependent cell death. Furthermore, they express very low levels of dMyc oncoprotein compared with those found in the surrounding normal tissue. Evidence that this is a cause of lgl mutant cells elimination was obtained by increasing dMyc levels in lgl mutant clones: their overgrowth potential was indeed re-established, with mutant cells overwhelming the neighbouring tissue and forming tumourous masses displaying several cancer hallmarks. Moreover, when lgl mutant clones were induced in backgrounds of slow-dividing cells, they upregulated dMyc, lost apical-basal cell polarity and were able to overgrow. Those phenotypes were abolished by reducing dMyc levels in the mutant clones, thereby confirming its key role in lgl-induced tumourigenesis. Furthermore, we show that the eiger-dependent Intrinsic Tumour Suppressor pathway plays only a minor role in eliminating lgl mutant cells in the wing pouch; lgl-/- clonal death in this region is instead driven mainly by dMyc-induced Cell Competition.ConclusionsOur results provide the first evidence that dMyc oncoprotein is required in lgl tumour suppressor mutant tissue to promote invasive overgrowth in larval and adult epithelial tissues. Moreover, we show that dMyc abundance inside versus outside the mutant clones plays a key role in driving neoplastic overgrowth.

【 授权许可】

Unknown   
© Froldi et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.