1.1. Tumor suppressor genes, a historical perspective
Cancer is essentially considered as a genetic disease caused by the accumulation of multiple genetic or epigenetic lesions in tumor-suppressor genes and oncogenes . Although the notion that retinoblastoma could be an inherited disease was already formulated at the end of the 19th Century a solid genetic basis was established with the discovery of both proto-oncogenes, whose gain-of function mutations or altered expression is associated with the cancerous state, and tumor suppressor genes (TSGs), whose inactivation releases the “brakes” inhibiting cell proliferation. Analysis of both proto-oncogenes and TSGs revealed also that cancer results from an alteration of the normal pathway of cell fate and differentiation. The hallmarks of cancer, as laid down by Hanahan and Weinberg to explain the complex biology of cancer, comprise six major developmental changes taking successively place in human tumors. These cancer “characteristics” include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis as well as cell invasion and metastasis. Underlying these hallmarks are genome instability, inflammation, reprogramming of energy metabolism and evading immune destruction .
Cancer cells are the foundation of the cancer disease, as they initiate formation of tumors and drive tumor progression forward. Based on the sequence of events in which cells accumulate genetic lesions, tumor progression and metastasis are highly variable, even among tumors of the same type . Previously, cancer cells within tumors were thought to be largely made of homogenous cells until relatively late in the course of tumor progression, when hyperproliferation combined with increased genetic instability spawn distinct clonal populations. Now we know that tumors rather than homogenous masses of proliferating cancer cells are complex tissues composed of distinct cell types participating in heterotypic interactions with each another. Reflecting such clonal heterogeneity is the finding that many human tumors display a complex histological pattern, characterized by regions exhibiting various degrees of differentiation, proliferation, vascularity, inflammation and invasiveness . In addition, tumors exhibit another dimension of complexity arising from the surrounding normal cells of the “tumor microenvironment”  (analyzed in part 3).
Over the last decades the origin of oncogenesis has been the subject of different theoretical “fashions”. In the current view taking into account the role of oncogenes and tumor suppressor genes cancer results from a failure occurring more in the control of cell differentiation than in cell proliferation [4, 5]. Nowadays, cancer is generally considered to result from a block or an error in the normal progression of differentiation. As a result, the cancer cells escape the mechanisms controlling normal growth and proliferation. Several decades ago, pioneer studies in the field of
1.1.1. Identification of the first tumor suppressor genes in
Over the past 40 years it has become increasingly evident that cancer is causally related to mutations in specific genes. These genes are instrumental to developmental processes such as cell-cell communication, signal transduction, regulation of gene expression, translation, cytoskeletal organization, protein folding and transport, and differential regulation of cell cycle . The
Recent contributions show that the Lgl protein may directly contribute to genetic regulation in association with the heavy chain of nonmuscle myosin II, or nmMHC [23, 24]. In particular mutations in
Subsequently to these initial studies, Gateff isolated a series of other recessive mutations in distinct genetic loci, which gave rise to four specific types of tumors. These tumors affected either the developing larval brain, the imaginal discs, the hematopoietic organs, or the germ cells [25, 26]. Shortly after
Drosophila as a unique model system to study tumor suppression
In order for an animal species to serve as a model of human biology it must fulfill two key criteria. The model system should be amenable to a broad set of experimental approaches and to be similar enough to humans so that findings from the model system can be exported to higher organisms and facilitate research in humans.
There are also many technical advantages in using
Drosophila in a century of “tool-building” research
The first documented use of
Interestingly, researches realized in the early fifties that genetic approaches could be used to study problems other than heredity. The continuous development of research tools between the years 1960-2010 has driven numerous new discoveries in fruit flies. In the mid-seventies, the available genetic tools in
The range of genetic tools that have become available for
The use of P-element-mediated transformation, available since 1982  has allowed the insertion of single genes and any DNA fragment of interest in the fly genome, and has opened the field to even more sophisticated genetic manipulations . This technique was significantly improved with the P[acman] technology that allows the insertion DNA fragments in specific docking sites spread throughout the
Another use of the P-element-mediated transformation facilitated the development of the
Finally, P-element technology also allowed the tagging of most genes
Drosophila is a model system relevant to human biology
The similarities between flies and humans are further supported by the fact that components of signal transduction pathways and the molecular mechanisms involved in specification, development, cell cycle regulation and human diseases were first identified in flies. The genes, which have been characterized in flies, were subsequently studied in mice and humans, and their names were adopted or adapted from their
3. Recent advances in modeling tumor progression and metastasis in
Since the discovery of oncogenes and tumor suppressor genes, intense research in many laboratories all over the world has brought us to the point where we are starting to understand the main principles underlying molecular changes in the course of tumor progression [3, 75]. The development of new technologies revealed the complex molecular nature of tumorigenesis in which tumor progression can be envisaged as a network of simultaneous events within both tumor cells and the stroma. Because cancer is an age-associated disease in humans, using
In addition to the importance of tumor cells themselves, their neighboring cells and the surrounding stroma are now recognized as important regulators of cancer progression . Cell competition is a type of short-range cell-cell interaction in which cells expressing different levels of a particular protein are able to discriminate between their relative levels so that the one cell, the “loser”, disappears from the tissue whereas the other, the “winner”, survives and proliferates to cover the space left by the disappearing cell. Some tumor-promoting mutations in
3.1. Modeling cell competition and metastasis
With these added complexities in mind, the analysis of cancer-disposing mutations in only a subset of cells or in clones within the context of a wild type surrounding tissue is gaining more interest because it offers a reasonable approximation of the clonal nature of human cancers, compared to the analysis of the multi-step model of tumor progression in the context of a whole organism. A great number of very interesting publications provided us with information about new and unexpected findings on the role of the polarity genes
Mutations inactivating the Salvator-Warts-Hippo (Sav-Wts-Hpo) pathway can also cause super-competition, contributing to the overgrowth of cells expressing these mutations in the presence of wild type cells [80, 103]. Since the first discovery of the Sav-Wts-Hpo pathway in
In the model of Scrib tumorigenesis, induction of apoptosis in
Among the wide palette of cellular events leading to JNK activation is the dTNF (tumor necrosis factor)/Eiger. Eiger is the only
Until very recently, the mechanism by which surrounding normal tissue exerts antitumor effects against
Drosophila provides critical insights on how conserved mechanisms contribute in cancer and tumorous development
The usefulness of
|2||Short life cycle|
|3||High fecundity (produce large number of off-springs with feature-rich morphology)|
|5||No ethical issues and regulatory considerations.|
• flies have only 4 pairs of chromosomes
• males lack genetic recombination, making genetic crosses easier
• flies tend to lack genetic redundancy
|7||Signaling pathways controlling growth, differentation and development, which are involved in tumor formation in the fly are largely conserved between
|8||Availability of numerous genetic tools & reagents for generating mutants and analysis of gene expression by using methods producing over- & ectopic- expression.
• The use of “balancer chromosomes” with multiple DNA inversions prevent female recombination and allows the perdurability of mutations on the original carrier chromosome
• Wide variety of gene targeting strategies, e.g. UAS-GAL4 system combined with RNAi knock-down allow the tissue-specific analysis of tumor suppressor gene and oncogene function
• Mosaic analysis of animals containing mutant clones next to wild type tissue, using FLP-FRT and MARCM recombination systems, allows the analysis of tumor microenvironment in invasion, metastasis & inflammation.
|9||Possibility to perform genome-wide screens using chemical mutagenesis, tissue-specific RNAi knockdown, effectors and modifier screens to identify genes involved in specific developmental pathways and assign and validate new gene functions.|
Interesting results using a
Furthermore, genetic analysis of border cell migration in the
Numerous molecules identified in
4. New perspectives in modeling tumorigenesis in
The remarkable degree in conservation of biochemical pathways that control processes such as cell proliferation, differentiation and migration as well as nervous system function in behavior and cognition, sustains perfectly the use of invertebrate model genetic organisms as tools for drug discovery and validation .
Furthermore, performing drug screening in the
Several groups today develop the associated technology to use
When the development of mosaic tissues is essential for the analyses of a disease model, the use of MARCM provides notable advantages for effective drug discovery. One is the ability to follow the morphology of mutant cells and tissues which could be useful for assessing the efficacy of a therapeutic compound . When a mutation in a given gene causally produces a disease, it is possible that this mutation elicits a change in expression of other genes and in the function of proteins. These alterations may contribute to the pathologies associated with the disease. The characterization of these changes constitutes then the first step needed to develop rational therapeutic strategies. Finally, the MARCM methodology should provide ways to identify mutant cells or tissues for a given gene, isolate and subject them to proteomic and genomic analyses which would determine modifications in gene expression and protein interaction profiles .
The phenotypes of complex trait diseases such as obesity, heart disease and cancer are the result of modifications occurring in multiple biochemical pathways. The disease phenotype can be caused by improper activation or inhibition of a protein that acts in any of the contributing pathways. Restoration of the normal phenotype would be expected if the output from the primary biochemical pathway affected is rescued via drug-based therapy . However, if multiple pathways contribute to a phenotype, it stands to reason that modifying the activity of a parallel pathway could also elicit a positive therapeutic effect. The use of genetic model organisms has long been a successful means for elucidation of biochemical and physiological pathways, and one of the most powerful strategies available for uncovering genes that act together in producing a phenotype is a search for genetic interaction or a modifier screen. Modifier screens work by generating animals with a mutation in a gene of interest that elicits a sensitized phenotype, and then screening for mutations in progeny that enhance or suppress (i.e., modify) the primary phenotype .
Drug discovery has also proved very effective for the identification of cancer treatments such as the multiple endocrine neoplasia type-2 (MEN2) [129, 162]. MEN2 is a “one-hit” solid tumor syndrome, characterized by mutations in the Ret protein, a transmembrane receptor tyrosine kinase. Patients with mutated oncogenic isoforms of Ret, develop medullary thyroid carcinomas (MTC) that lead to metastasis, which seem to be resistant to traditional chemotherapies. To develop a whole-animal transgenic model, various oncogenic Ret isoforms were targeted to the developing fly eye epithelium. The fly ”rough-eye” phenotype is characterized by eye overgrowth, switch in cell fate and other aspects, proving the effectiveness of fly as model and useful readout for screening. The screening for clinical relevant compounds led in the tumorous developing flies by Cagan and his group resulted in the identification of Vandetanib, a broad kinase inhibitor, which Cagan called “the worst kinase inhibitor”. Although not very specific and effective, this kinase inhibitor was indeed effective in rescuing the fly phenotype because it regulated the activity of other kinases such as Ras, Src and PI3K (all of which are involved in cancer). Other compounds were more capable of rescuing the rough eye phenotype but reduced animal viability. Yet, Vandetanib displayed little toxicity to the animal as a whole, indicating that tumors might display a lower tolerance threshold for drugs than the entire animal. Obviously the “off-target” effects of Vandetanib, by suppressing kinases other than Ret, are important for its effectiveness. Classical drug screenings would reject Vandetanib as too inefficient to the target and too low in its specificity [129, 162]. Cell-culture and subsequent fly work proved to be extremely valuable, as Vandetanib was shown to be efficient in Phase II clinical trials, Currently Vandetanib is in Phase III of clinical assays. This further proves the power of
5. Limitations in using
Drosophila as a model system: how far can we go?
Are there limitations in using
Often model systems are used to understand life and basic biological and cellular mechanisms. A better understanding of a specific human disease often comes as a consequence of the better overall understanding of biological processes . Within this context,
6. The expanding role of
Drosophila in cancer research: Bridging past, present and future
Undeniably the study of
AcknowledgmentsWe apologize to all whose work has not been sited due to space limitations. This work was supported by the “Zentraler Forschungspool” funding of the University of Heidelberg to F.P. and the Czech Grant Foundation P302/11/1640, the Charles University Center UNCE204022 and the First Faculty of Medicine Prvouk/1LF/1 to B.M.M.
Kango-Singh M, Halder G. Drosophila as an emerging model to study metastasis. Genome Biol. 2004;5(4):216.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.
Bhatt AM, Zhang Q, Harris SA, White-Cooper H, Dickinson H. Gene structure and molecular analysis of Arabidopsis thaliana ALWAYS EARLY homologs. Gene. 2004 Jul 21;336(2):219-29.
Harris H. A long view of fashions in cancer research. Bioessays. 2005 Aug;27(8):833-8.
Gateff E, Schneiderman HA. Developmental studies of a new mutant of Drosophila melanogaster lethal malignant brain tumor (l(2)gl4). Am Zool. 1967;7:760.
Gateff E, Schneiderman HA. Neoplasms in mutant and cultured wild-tupe tissues of Drosophila. Natl Cancer Inst Monogr. 1969 Jul;31:365-97.
Harris H, Miller OJ, Klein G, Worst P, Tachibana T. Suppression of malignancy by cell fusion. Nature. 1969 Jul 26;223(5204):363-8.
Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3.
Mechler BM, McGinnis W, Gehring WJ. Molecular cloning of lethal(2)giant larvae, a recessive oncogene of Drosophila melanogaster. EMBO J. 1985 Jun;4(6):1551-7.
Mechler BM, Torok I, Schmidt M, Opper M, Kuhn A, Merz R, et al. Molecular basis for the regulation of cell fate by the lethal (2) giant larvae tumour suppressor gene of Drosophila melanogaster. Ciba Found Symp. 1989;142:166-78; discussion 78-80.
Gateff E. Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects. Int J Dev Biol. 1994 Dec;38(4):565-90.
Bridges CB, Brehme KS. The mutants of Drosophila melanogaster: Carnegie Institution; 1944.
Gateff E SH. Developmental capacities of benign and malignant neoplasms of Drosophila. Wilhelm Roux’ Archiv. 1974;176(23-65).
Opper M, Schuler G, Mechler BM. Hereditary suppression of lethal (2) giant larvae malignant tumor development in Drosophila by gene transfer. Oncogene. 1987 May;1(2):91-6.
Merz R, Schmidt M, Torok I, Protin U, Schuler G, Walther HP, et al. Molecular action of the l(2)gl tumor suppressor gene of Drosophila melanogaster. Environ Health Perspect. 1990 Aug;88:163-7.
Torok I, Hartenstein K, Kalmes A, Schmitt R, Strand D, Mechler BM. The l(2)gl homologue of Drosophila pseudoobscura suppresses tumorigenicity in transgenic Drosophila melanogaster. Oncogene. 1993 Jun;8(6):1537-49.
Strand D, Jakobs R, Merdes G, Neumann B, Kalmes A, Heid HW, et al. The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain. J Cell Biol. 1994 Dec;127(5):1361-73.
Strand D, Raska I, Mechler BM. The Drosophila lethal(2)giant larvae tumor suppressor protein is a component of the cytoskeleton. J Cell Biol. 1994 Dec;127(5):1345-60.
Kalmes A, Merdes G, Neumann B, Strand D, Mechler BM. A serine-kinase associated with the p127-l(2)gl tumour suppressor of Drosophila may regulate the binding of p127 to nonmuscle myosin II heavy chain and the attachment of p127 to the plasma membrane. J Cell Sci. 1996 Jun;109 ( Pt 6):1359-68.
Strand D. The Tumor Suppressor l(2)gl: A Myosin-Binding Protein Family. Kohama HMaK, editor: R. G. Landes Company; 1998.
Li M, Strand D, Krehan A, Pyerin W, Heid H, Neumann B, et al. Casein kinase 2 binds and phosphorylates the nucleosome assembly protein-1 (NAP1) in Drosophila melanogaster. J Mol Biol. 1999 Nov 12;293(5):1067-84.
Farkas R, Mechler BM. The timing of drosophila salivary gland apoptosis displays an l(2)gl-dose response. Cell Death Differ. 2000 Jan;7(1):89-101.
Farkas R, Kucharova-Mahmood S, Mentelova L, Juda P, Raska I, Mechler B. Cytoskeletal proteins regulate chromatic access of BR-C transcription factor and Rpd3-Sin3A histone deacetylase complex in Drosophila salivary glands. Nucleus. 2011:(in print).
Gateff E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science. 1978 Jun 30;200(4349):1448-59.
Gateff E. Cancer, genes, and development: the Drosophila case. Adv Cancer Res. 1982;37:33-74.
Stewart M, Murphy C, Fristrom JW. The recovery and preliminary characterization of X chromosome mutants affecting imaginal discs of Drosophila melanogaster. Dev Biol. 1972 Jan;27(1):71-83.
Gateff E. Malignant neoplasms of the hematopoietic system in three mutants of Drosophila melanogaster. Ann Parasitol Hum Comp. 1977 Jan-Feb;52(1):81-3.
Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature. 2000 Feb 10;403(6770):676-80.
Li M, Marhold J, Gatos A, Torok I, Mechler BM. Differential expression of two scribble isoforms during Drosophila embryogenesis. Mech Dev. 2001 Oct;108(1-2):185-90.
Jennings BH. Drosophila-a versatile model in biology & medicine. materials today. 2011;14(5):190-5.
Stocker H, Gallant P. Getting started : an overview on raising and handling Drosophila. Methods Mol Biol. 2008;420:27-44.
Kohler RE. Lords of the fly: Drosophila genetics and the experimental life. Chicago: University of Chicago Press; 1994.
Morgan TH. Sex Limited Inheritance in Drosophila. Science. 1910 Jul 22;32(812):120-2.
Green MM. 2010: A century of Drosophila genetics through the prism of the white gene. Genetics. 2010 Jan;184(1):3-7.
Muller HJ. The Measurement of Gene Mutation Rate in Drosophila, Its High Variability, and Its Dependence upon Temperature. Genetics. 1928 May;13(4):279-357.
Bellen HJ, Tong C, Tsuda H. 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci. 2010 Jul;11(7):514-22.
Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980 Oct 30;287(5785):795-801.
Wieschaus E, Nusslein-Volhard C, Kluding H. Kruppel, a gene whose activity is required early in the zygotic genome for normal embryonic segmentation. Dev Biol. 1984 Jul;104(1):172-86.
Jurgens G, Wieschaus E, Nusslein-Volhard C, Kluding H. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. Rouxs Arch Dev Biol. 1984;193:283-95.
Lewis EB, Bacher F. Methods of feeding ethyl methane sulfonate (EMS) to Drosophila males. Inf Serv. 1968;43(193):193.
Hobert O. The impact of whole genome sequencing on model system genetics: get ready for the ride. Genetics. 2010 Feb;184(2):317-9.
Bellen HJ, Levis RW, Liao G, He Y, Carlson JW, Tsang G, et al. The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics. 2004 Jun;167(2):761-81.
Rong YS, Titen SW, Xie HB, Golic MM, Bastiani M, Bandyopadhyay P, et al. Targeted mutagenesis by homologous recombination in D. melanogaster. Genes Dev. 2002 Jun 15;16(12):1568-81.
Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature. 2007 Jul 12;448(7150):151-6.
Ni JQ, Liu LP, Binari R, Hardy R, Shim HS, Cavallaro A, et al. A Drosophila resource of transgenic RNAi lines for neurogenetics. Genetics. 2009 Aug;182(4):1089-100.
Rubin GM, Spradling AC. Genetic transformation of Drosophila with transposable element vectors. Science. 1982 Oct 22;218(4570):348-53.
Venken KJ, He Y, Hoskins RA, Bellen HJ. P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science. 2006 Dec 15;314(5806):1747-51.
Groth AC, Fish M, Nusse R, Calos MP. Construction of transgenic Drosophila by using the site-specific integrase from phage phiC31. Genetics. 2004 Apr;166(4):1775-82.
Golic KG, Lindquist S. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell. 1989 Nov 3;59(3):499-509.
Golic KG. Site-specific recombination between homologous chromosomes in Drosophila. Science. 1991 May 17;252(5008):958-61.
Bell AJ, McBride SM, Dockendorff TC. Flies as the ointment: Drosophila modeling to enhance drug discovery. Fly (Austin). 2009 Jan-Mar;3(1):39-49.
Lee T, Luo L. Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 2001 May;24(5):251-4.
Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993 Jun;118(2):401-15.
Pfeiffer BD, Jenett A, Hammonds AS, Ngo TT, Misra S, Murphy C, et al. Tools for neuroanatomy and neurogenetics in Drosophila. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9715-20.
Margadant C, Raymond K, Kreft M, Sachs N, Janssen H, Sonnenberg A. Integrin alpha3beta1 inhibits directional migration and wound re-epithelialization in the skin. J Cell Sci. 2009 Jan 15;122(Pt 2):278-88.
McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL. Spatiotemporal rescue of memory dysfunction in Drosophila. Science. 2003 Dec 5;302(5651):1765-8.
McGuire SE, Mao Z, Davis RL. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci STKE. 2004 Feb 17;2004(220):pl6.
Venken KJ, Bellen HJ. Transgenesis upgrades for Drosophila melanogaster. Development. 2007 Oct;134(20):3571-84.
Morin X, Daneman R, Zavortink M, Chia W. A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15050-5.
Kelso RJ, Buszczak M, Quinones AT, Castiblanco C, Mazzalupo S, Cooley L. Flytrap, a database documenting a GFP protein-trap insertion screen in Drosophila melanogaster. Nucleic Acids Res. 2004 Jan 1;32(Database issue):D418-20.
Buszczak M, Paterno S, Lighthouse D, Bachman J, Planck J, Owen S, et al. The carnegie protein trap library: a versatile tool for Drosophila developmental studies. Genetics. 2007 Mar;175(3):1505-31.
Quinones-Coello AT, Petrella LN, Ayers K, Melillo A, Mazzalupo S, Hudson AM, et al. Exploring strategies for protein trapping in Drosophila. Genetics. 2007 Mar;175(3):1089-104.
Miles A, Zhao J, Klyne G, White-Cooper H, Shotton D. OpenFlyData: an exemplar data web integrating gene expression data on the fruit fly Drosophila melanogaster. J Biomed Inform. 2010 Oct;43(5):752-61.
Singh A, Irvine KD. Drosophila as a model for understanding development and disease. Dev Dyn. 2012 Jan;241(1):1-2.
Gilbert LI. Drosophila is an inclusive model for human diseases, growth and development. Mol Cell Endocrinol. 2008 Oct 10;293(1-2):25-31.
Schneider D. Using Drosophila as a model insect. Nat Rev Genet. 2000 Dec;1(3):218-26.
Botas J. Drosophila researchers focus on human disease. Nat Genet. 2007 May;39(5):589-91.
Pfleger CM, Reiter LT. Recent efforts to model human diseases in vivo in Drosophila. Fly (Austin). 2008 May-Jun;2(3):129-32.
Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 2001 Jun;11(6):1114-25.
McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283-302.
Miklos GL, Rubin GM. The role of the genome project in determining gene function: insights from model organisms. Cell. 1996 Aug 23;86(4):521-9.
Venken KJ, Carlson JW, Schulze KL, Pan H, He Y, Spokony R, et al. Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nat Methods. 2009 Jun;6(6):431-4.
Tenenbaum D. What's All the Buzz? Fruit Flies Provide Unique Model for Cancer Research. J Natl Cancer Inst. 2003 Dec 3;95(23):1742-4.
Crnic I, Christofori G. Novel technologies and recent advances in metastasis research. Int J Dev Biol. 2004;48(5-6):573-81.
Vidal M. The dark side of fly TNF: an ancient developmental proof reading mechanism turned into tumor promoter. Cell Cycle. 2010 Oct 1;9(19):3851-6.
Junttila MR, Evan GI. p53--a Jack of all trades but master of none. Nat Rev Cancer. 2009 Nov;9(11):821-9.
Miles WO, Dyson NJ, Walker JA. Modeling tumor invasion and metastasis in Drosophila. Dis Model Mech. 2011 Nov;4(6):753-61.
Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001 Oct;1(1):46-54.
Moreno E. Is cell competition relevant to cancer? Nat Rev Cancer. 2008 Feb;8(2):141-7.
Brumby AM, Richardson HE. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer. 2005 Aug;5(8):626-39.
Humbert PO, Grzeschik NA, Brumby AM, Galea R, Elsum I, Richardson HE. Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene. 2008 Nov 24;27(55):6888-907.
Mohamet L, Hawkins K, Ward CM. Loss of function of e-cadherin in embryonic stem cells and the relevance to models of tumorigenesis. J Oncol. 2011;2011:352616.
Pagliarini RA, Xu T. A genetic screen in Drosophila for metastatic behavior. Science. 2003 Nov 14;302(5648):1227-31.
Schmeichel KL. A fly's eye view of tumor progression and metastasis. Breast Cancer Res. 2004;6(2):82-3.
Woodhouse EC, Liotta LA. Drosophila invasive tumors: a model for understanding metastasis. Cell Cycle. 2004 Jan;3(1):38-40.
Parisi F, Vidal M. Epithelial delamination and migration: lessons from Drosophila. Cell Adh Migr. 2011 Jul-Aug;5(4):366-72.
Van Dyke T, Jacks T. Cancer modeling in the modern era: progress and challenges. Cell. 2002 Jan 25;108(2):135-44.
Balmain A. Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell. 2002 Jan 25;108(2):145-52.
St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet. 2002 Mar;3(3):176-88.
Blair SS. Genetic mosaic techniques for studying Drosophila development. Development. 2003 Nov;130(21):5065-72.
Kornberg TB, Krasnow MA. The Drosophila genome sequence: implications for biology and medicine. Science. 2000 Mar 24;287(5461):2218-20.
Rubin GM, Lewis EB. A brief history of Drosophila's contributions to genome research. Science. 2000 Mar 24;287(5461):2216-8.
Tanenbaum DM. What's All the Buzz? Fruit Flies Provide Unique Model for Cancer Research. Journal of the National Cancer Institute. 2003;95(23):1742-4.
Brumby AM, Richardson HE. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 2003 Nov 3;22(21):5769-79.
Leong GR, Goulding KR, Amin N, Richardson HE, Brumby AM. Scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs. BMC Biol. 2009;7:62.
Etienne-Manneville S. Scribble at the crossroads. J Biol. 2009;8(12):104.
Tapon N. Modeling transformation and metastasis in Drosophila. Cancer Cell. 2003 Nov;4(5):333-5.
Vidal M, Salavaggione L, Ylagan L, Wilkins M, Watson M, Weilbaecher K, et al. A role for the epithelial microenvironment at tumor boundaries: evidence from Drosophila and human squamous cell carcinomas. Am J Pathol. 2010 Jun;176(6):3007-14.
Wu M, Pastor-Pareja JC, Xu T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature. 2010 Jan 28;463(7280):545-8.
Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 2012 Jan;12(1):23-38.
Igaki T, Pagliarini RA, Xu T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol. 2006 Jun 6;16(11):1139-46.
Tyler DM, Li W, Zhuo N, Pellock B, Baker NE. Genes affecting cell competition in Drosophila. Genetics. 2007 Feb;175(2):643-57.
Hariharan IK, Bilder D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev Genet. 2006;40:335-61.
Harvey K, Tapon N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer. 2007 Mar;7(3):182-91.
Saucedo LJ, Edgar BA. Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007 Aug;8(8):613-21.
Bennett FC, Harvey KF. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol. 2006 Nov 7;16(21):2101-10.
Silva EA, Lee BJ, Caceres LS, Renouf D, Vilay BR, Yu O, et al. A novel strategy for identifying mutations that sensitize Drosophila eye development to caffeine and hydroxyurea. Genome. 2006 Nov;49(11):1416-27.
Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, et al. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol. 2006 Nov 7;16(21):2090-100.
Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 2010 Feb 16;18(2):288-99.
Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N. Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell. 2010 Feb 16;18(2):300-8.
Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H. The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell. 2010 Feb 16;18(2):309-16.
Doggett K, Grusche FA, Richardson HE, Brumby AM. Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling. BMC Dev Biol. 2011;11:57.
Chen CL, Schroeder MC, Kango-Singh M, Tao C, Halder G. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):484-9.
Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol. 2010 Apr 13;20(7):573-81.
Grzeschik NA, Parsons LM, Richardson HE. Lgl, the SWH pathway and tumorigenesis: It's a matter of context & competition! Cell Cycle. 2010 Aug 15;9(16):3202-12.
Tamori Y, Bialucha CU, Tian AG, Kajita M, Huang YC, Norman M, et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 2010;8(7):e1000422.
Mair W. How normal cells can win the battle for survival against cancer cells. PLoS Biol. 2010;8(7):e1000423.
Alderton GK. Tumorigenesis: To the death! Nat Rev Cancer. 2010 Sep;10(9):598.
Menendez J, Perez-Garijo A, Calleja M, Morata G. A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14651-6.
Froldi F, Ziosi M, Garoia F, Pession A, Grzeschik NA, Bellosta P, et al. The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol. 2010;8:33.
Zhu M, Xin T, Weng S, Gao Y, Zhang Y, Li Q, et al. Activation of JNK signaling links lgl mutations to disruption of the cell polarity and epithelial organization in Drosophila imaginal discs. Cell Res. 2010 Feb;20(2):242-5.
Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010 Apr 13;20(7):582-90.
Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7.
Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15810-5.
Cordero JB, Macagno JP, Stefanatos RK, Strathdee KE, Cagan RL, Vidal M. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell. 2010 Jun 15;18(6):999-1011.
Igaki T. Correcting developmental errors by apoptosis: lessons from Drosophila JNK signaling. Apoptosis. 2009 Aug;14(8):1021-8.
Ohsawa S, Sugimura K, Takino K, Xu T, Miyawaki A, Igaki T. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev Cell. 2011 Mar 15;20(3):315-28.
Rudrapatna VA, Cagan RL, Das TK. Drosophila cancer models. Dev Dyn. 2012 Jan;241(1):107-18.
Chang KC, Wang C, Wang H. Balancing self-renewal and differentiation by asymmetric division: insights from brain tumor suppressors in Drosophila neural stem cells. Bioessays. 2012 Apr;34(4):301-10.
Gonczy P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nat Rev Mol Cell Biol. 2008 May;9(5):355-66.
Iden S, van Riel WE, Schafer R, Song JY, Hirose T, Ohno S, et al. Tumor type-dependent function of the par3 polarity protein in skin tumorigenesis. Cancer Cell. 2012 Sep 11;22(3):389-403.
Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009 Aug;9(8):550-62.
Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol. 2012 Aug 10;30(23):2919-28.
Read RD. Drosophila melanogaster as a model system for human brain cancers. Glia. 2011 Sep;59(9):1364-76.
Caldeira J, Pereira PS, Suriano G, Casares F. Using fruitflies to help understand the molecular mechanisms of human hereditary diffuse gastric cancer. Int J Dev Biol. 2009;53(8-10):1557-61.
Pereira PS, Teixeira A, Pinho S, Ferreira P, Fernandes J, Oliveira C, et al. E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Hum Mol Genet. 2006 May 15;15(10):1704-12.
Crozatier M, Vincent A. Drosophila: a model for studying genetic and molecular aspects of haematopoiesis and associated leukaemias. Dis Model Mech. 2011 Jul;4(4):439-45.
Zhai Z, Ha N, Papagiannouli F, Hamacher-Brady A, Brady N, Sorge S, et al. Antagonistic regulation of apoptosis and differentiation by the Cut transcription factor represents a tumor-suppressing mechanism in Drosophila. PLoS Genet. 2012 Mar;8(3):e1002582.
Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005 May;5(5):355-66.
Naora H. Developmental patterning in the wrong context: the paradox of epithelial ovarian cancers. Cell Cycle. 2005 Aug;4(8):1033-5.
Duchek P, Somogyi K, Jekely G, Beccari S, Rorth P. Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell. 2001 Oct 5;107(1):17-26.
Bartlett JM, Langdon SP, Simpson BJ, Stewart M, Katsaros D, Sismondi P, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996 Feb;73(3):301-6.
Sundfeldt K, Piontkewitz Y, Ivarsson K, Nilsson O, Hellberg P, Brannstrom M, et al. E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int J Cancer. 1997 Jun 20;74(3):275-80.
Sundfeldt K. Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. Mol Cell Endocrinol. 2003 Apr 28;202(1-2):89-96.
Marques FR, Fonsechi-Carvasan GA, De Angelo Andrade LA, Bottcher-Luiz F. Immunohistochemical patterns for alpha- and beta-catenin, E- and N-cadherin expression in ovarian epithelial tumors. Gynecol Oncol. 2004 Jul;94(1):16-24.
Edwards PA. The impact of developmental biology on cancer research: an overview. Cancer Metastasis Rev. 1999;18(2):175-80.
Ng JM, Curran T. The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer. 2011 Jul;11(7):493-501.
Cordero JB, Sansom OJ. Wnt signalling and its role in stem cell-driven intestinal regeneration and hyperplasia. Acta Physiol (Oxf). 2012 Jan;204(1):137-43.
Jessen S, Gu B, Dai X. Pygopus and the Wnt signaling pathway: a diverse set of connections. Bioessays. 2008 May;30(5):448-56.
Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003 Oct;3(10):756-67.
Bossuyt W, De Geest N, Aerts S, Leenaerts I, Marynen P, Hassan BA. The atonal proneural transcription factor links differentiation and tumor formation in Drosophila. PLoS Biol. 2009 Feb 24;7(2):e40.
Berthold J, Schenkova K, Rivero F. Rho GTPases of the RhoBTB subfamily and tumorigenesis. Acta Pharmacol Sin. 2008 Mar;29(3):285-95.
Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005 Jan;5(1):51-63.
Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009 Feb;9(2):108-22.
Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010 May;10(5):361-71.
Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, Lappin TR. The pathophysiology of HOX genes and their role in cancer. J Pathol. 2005 Jan;205(2):154-71.
Giacomotto J, Segalat L. High-throughput screening and small animal models, where are we? Br J Pharmacol. 2010 May;160(2):204-16.
Aitman TJ, Boone C, Churchill GA, Hengartner MO, Mackay TF, Stemple DL. The future of model organisms in human disease research. Nat Rev Genet. 2011 Aug;12(8):575-82.
Pandey UB, Nichols CD. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev. 2011 Jun;63(2):411-36.
Segalat L. Invertebrate animal models of diseases as screening tools in drug discovery. ACS Chem Biol. 2007 Apr 24;2(4):231-6.
Kasai Y, Cagan R. Drosophila as a tool for personalized medicine: a primer. Per Med. 2010 Nov;7(6):621-32.
Perrimon N, Friedman A, Mathey-Prevot B, Eggert US. Drug-target identification in Drosophila cells: combining high-throughout RNAi and small-molecule screens. Drug Discov Today. 2007 Jan;12(1-2):28-33.
Bier E. Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet. 2005 Jan;6(1):9-23.
Wolf MJ, Rockman HA. Drosophila melanogaster as a model system for genetics of postnatal cardiac function. Drug Discov Today Dis Models. 2008 Oct 1;5(3):117-23.
Chien S, Reiter LT, Bier E, Gribskov M. Homophila: human disease gene cognates in Drosophila. Nucleic Acids Res. 2002 Jan 1;30(1):149-51.
Kaletta T, Hengartner MO. Finding function in novel targets: C. elegans as a model organism. Nat Rev Drug Discov. 2006 May;5(5):387-98.
Roeder T, Isermann K, Kabesch M. Drosophila in asthma research. Am J Respir Crit Care Med. 2009 Jun 1;179(11):979-83.
Kharchenko PV, Alekseyenko AA, Schwartz YB, Minoda A, Riddle NC, Ernst J, et al. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature. 2011 Mar 24;471(7339):480-5.
Furlong EE. Molecular biology: A fly in the face of genomics. Nature. 2011 Mar 24;471(7339):458-9.
Beller M, Oliver B. One hundred years of high-throughput Drosophila research. Chromosome Res. 2006;14(4):349-62.
Negre N, Brown CD, Ma L, Bristow CA, Miller SW, Wagner U, et al. A cis-regulatory map of the Drosophila genome. Nature. 2011 Mar 24;471(7339):527-31.
Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, Yang L, et al. The developmental transcriptome of Drosophila melanogaster. Nature. 2011 Mar 24;471(7339):473-9.
Chintapalli VR, Wang J, Dow JA. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet. 2007 Jun;39(6):715-20.