Human tumours have a large degree of cellular and genetic heterogeneity1. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression2. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development3; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations4, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein RasV12 (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib)6,7 gives rise to metastatic tumours that display many characteristics observed in human cancers8,9,10,11. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the RasV12 and scrib- mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between RasV12 and scrib- clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of RasV12 tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.
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We thank E. Bach, D. Harrison, J. Castelli-Gair Hombria, M. Zeidler, T. Adachi-Yamada, M. Mlodzik, E. Matunis, D. Montell, H. Agaisse, the Bloomington Stock Center and the National Institute of Genetics (Kyoto) for fly strains, and T. Ni, S. Landrette and M. Rojas for comments. R. Pagliarini and S. Landrette helped with microarray analysis and RT–PCR. We thank T. Igaki for discussing the manuscript and providing FRT82B,tub-Gal80,scrib1/TM6B flies. M.W. is a Yale predoctoral fellow. J.C.P.-P. was funded by a Spanish Ministry of Education postdoctoral fellowship. This work was supported by a grant from NIH/NCI to T.X. T.X. is a Howard Hughes Medical Institute Investigator.
Author Contributions M.W., J.C.P.-P. and T.X. designed research, M.W. and J.C.P.-P. performed experiments and analysed the data. M.W., J.C.P.-P. and T.X. wrote the manuscript.