Abstract
In Drosophila imaginal epithelia, cells mutant for the endocytic neoplastic tumor suppressor gene vps25 stimulate nearby untransformed cells to express Drosophila Inhibitor-of-Apoptosis-Protein-1 (DIAP-1), conferring resistance to apoptosis non-cell autonomously. Here, we show that the non-cell autonomous induction of DIAP-1 is mediated by Yorkie, the conserved downstream effector of Hippo signaling. The non-cell autonomous induction of Yorkie is due to Notch signaling from vps25 mutant cells. Moreover, activated Notch in normal cells is sufficient to induce non-cell autonomous Yorkie activity in wing imaginal discs. Our data identify a novel mechanism by which Notch promotes cell survival non-cell autonomously and by which neoplastic tumor cells generate a supportive microenvironment for tumor growth.
Highlights
Imbalances in the cell-cell communication that coordinates cell proliferation, cell differentiation, and cell death can trigger cancer development
Most epithelial cancers arise from single cells that have acquired multiple oncogenic lesions while initially being surrounded by normal cells [1,2,3]
When mutant cells of these neoplastic tumor suppressor genes (nTSGs) are surrounded by wild-type cells, they undergo JNK-mediated cell death [6,13,14,15], and only if cell death is blocked, they unleash their tumorpromoting capacity [6,7]
Summary
Imbalances in the cell-cell communication that coordinates cell proliferation, cell differentiation, and cell death can trigger cancer development. We show that activation of Notch, but not of JNK or JAK/STAT, in vps25 mutant cells can induce non-cell autonomous protection from apoptosis by inducing expression of diap1.
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