Notch Mediates Inter-tissue Communication to Promote Tumorigenesis

Disease progression in many tumor types involves the interaction of genetically abnormal cancer cells with normal stromal cells. Neoplastic transformation in a Drosophila genetic model of epidermal growth factor receptor (EGFR)-driven tumorigenesis similarly relies on the interaction between epithelial and mesenchymal cells, providing a simple system to investigate mechanisms used for the cross-talk. Using the Drosophila model, we show that the transformed epithelium hijacks the mesenchymal cells through Notch signaling, which prevents their differentiation and promotes proliferation. A key downstream target in the mesenchyme is Zfh1/ZEB. When Notch or zfh1 are depleted in the mesenchymal cells, tumor growth is compromised. The ligand Delta is highly upregulated in the epithelial cells where it is found on long cellular processes. By using a live transcription assay in cultured cells and by depleting actin-rich processes in the tumor epithelium, we provide evidence that signaling can be mediated by cytonemes from Delta-expressing cells. We, thus, propose that high Notch activity in the unmodified mesenchymal cells is driven by ligands produced by the cancerous epithelial. This long-range Notch signaling integrates the two tissues to promote tumorigenesis, by co-opting a normal regulatory mechanism that prevents the mesenchymal cells from differentiating. •Notch promotes tumor growth through inter-tissue communication•Cancerous epithelial cells hijack the normal mesenchymal cells by Notch signaling•Delta from epithelial cells activates Notch in the mesenchyme through cytonemes•Zfh1/ZEB is upregulated by Notch and prevents mesenchymal differentiation Boukhatmi et al. use a simple Drosophila model to investigate how cancerous epithelial cells sustain tumor growth. Epithelial cytonemes provide Delta to co-opt the normal mesenchyme through long-range Notch activation. High mesenchymal Notch activity promotes proliferation and prevents differentiation to support tumor growth.