A Tumor-suppressing Mechanism in Drosophila Involving Cell Competition and the Hippo Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Aug 4

PMID 20679206

Citations 101

Authors

Javier Menendez

Ainhoa Perez-Garijo

Manuel Calleja

Gines Morata

Affiliations

Soon will be listed here.

Abstract

Mutant larvae for the Drosophila gene lethal giant larva (lgl) develop neoplastic tumors in imaginal discs. However, lgl mutant clones do not form tumors when surrounded by wild-type tissue, suggesting the existence of a tumor-suppressing mechanism. We have investigated the tumorigenic potential of lgl mutant cells by generating wing compartments that are entirely mutant for lgl and also inducing clones of various genetic combinations of lgl(-) cells. We find that lgl(-) compartments can grow indefinitely but lgl(-) clones are eliminated by cell competition. lgl mutant cells may form tumors if they acquire constitutive activity of the Ras pathway (lgl(-) UAS-ras(V12)), which confers proliferation advantage through inhibition of the Hippo pathway. Yet, the majority of lgl(-) UAS-ras(V12) clones are eliminated in spite of their high proliferation rate. The formation of a tumor requires in addition the formation of a microenvironment that allows mutant cells to evade cell competition.

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References

Mechler B, McGinnis W, Gehring W . Molecular cloning of lethal(2)giant larvae, a recessive oncogene of Drosophila melanogaster. EMBO J. 1985; 4(6):1551-7. PMC: 554381. DOI: 10.1002/j.1460-2075.1985.tb03816.x. View

Martin F, Morata G . Compartments and the control of growth in the Drosophila wing imaginal disc. Development. 2006; 133(22):4421-6. DOI: 10.1242/dev.02618. View

Karim F, Rubin G . Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development. 1997; 125(1):1-9. DOI: 10.1242/dev.125.1.1. View

Raff M . Social controls on cell survival and cell death. Nature. 1992; 356(6368):397-400. DOI: 10.1038/356397a0. View

Hariharan I, Bilder D . Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev Genet. 2006; 40:335-61. DOI: 10.1146/annurev.genet.39.073003.100738. View

Morata G, Ripoll P . Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol. 1975; 42(2):211-21. DOI: 10.1016/0012-1606(75)90330-9. View

Humbert P, Grzeschik N, Brumby A, Galea R, Elsum I, Richardson H . Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene. 2008; 27(55):6888-907. DOI: 10.1038/onc.2008.341. View

Igaki T, Pastor-Pareja J, Aonuma H, Miura M, Xu T . Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell. 2009; 16(3):458-65. PMC: 2729686. DOI: 10.1016/j.devcel.2009.01.002. View

Prober D, Edgar B . Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes Dev. 2002; 16(17):2286-99. PMC: 186666. DOI: 10.1101/gad.991102. View

10.

Simpson P, Morata G . Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. Dev Biol. 1981; 85(2):299-308. DOI: 10.1016/0012-1606(81)90261-x. View

11.

Moreno E, Basler K, Morata G . Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature. 2002; 416(6882):755-9. DOI: 10.1038/416755a. View

12.

Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky A, Martinez-Arias A . puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Genes Dev. 1998; 12(4):557-70. PMC: 316530. DOI: 10.1101/gad.12.4.557. View

13.

Adachi-Yamada T, OConnor M . Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen gradients. Dev Biol. 2002; 251(1):74-90. DOI: 10.1006/dbio.2002.0821. View

14.

Woods D, Bryant P . Molecular cloning of the lethal(1)discs large-1 oncogene of Drosophila. Dev Biol. 1989; 134(1):222-35. DOI: 10.1016/0012-1606(89)90092-4. View

15.

Milan M, Perez L, Cohen S . Short-range cell interactions and cell survival in the Drosophila wing. Dev Cell. 2002; 2(6):797-805. DOI: 10.1016/s1534-5807(02)00169-7. View

16.

Prober D, Edgar B . Ras1 promotes cellular growth in the Drosophila wing. Cell. 2000; 100(4):435-46. DOI: 10.1016/s0092-8674(00)80679-0. View

17.

Froldi F, Ziosi M, Garoia F, Pession A, Grzeschik N, Bellosta P . The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol. 2010; 8:33. PMC: 2877678. DOI: 10.1186/1741-7007-8-33. View

18.

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford S . Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007; 130(6):1120-33. PMC: 2666353. DOI: 10.1016/j.cell.2007.07.019. View

19.

Igaki T . Correcting developmental errors by apoptosis: lessons from Drosophila JNK signaling. Apoptosis. 2009; 14(8):1021-8. DOI: 10.1007/s10495-009-0361-7. View

20.

Brumby A, Richardson H . scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 2003; 22(21):5769-79. PMC: 275405. DOI: 10.1093/emboj/cdg548. View