Interaction between Ras(V12) and scribble clones induces tumour growth and invasion

Human tumours exhibit a large degree of cellular and genetic heterogeneity 1. Complex cell interactions in the tumour and its microenvironment are thought to play a significant role in tumourigenesis and cancer progression 2. It is also known that cooperation between oncogenic genetic lesions is required for tumour development 3. However, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruit fly Drosophila melanogaster allow analysis of the behavior of cells with distinct mutations 4, giving this model organism a privileged position to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein Ras(V12) 5 and loss-of-function mutations in the conserved tumour suppressor scribble (scrib) 6,7 gives rise to metastatic tumours that display many characteristics observed in human cancers 8-11. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the Ras(V12) and scrib(−) mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between Ras(V12) and scrib(−) clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumours can also be triggered by tissue damage, a stress condition that activates JNK signaling. Given the conservation of the pathways examined here, similar cooperative mechanisms could play a role in the development of human cancers.