Cell competition is a homeostatic process in which proliferating cells compete for survival. Elimination of otherwise normal healthy cells through competition is important during development and has recently been shown to contribute to maintaining tissue health during organismal aging. The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells expressing EGFR together with the conserved microRNA miR-8 acquire the properties of supercompetitors. Neoplastic transformation and metastasis depend on the ability of these cells to induce apoptosis and engulf nearby cells. miR-8 expression causes genome instability by downregulating expression of the Septin family protein Peanut. Cytokinesis failure due to downregulation of Peanut is required for tumorigenesis. This study provides evidence that the cellular mechanisms that drive cell competition during normal tissue growth can be co-opted to drive tumor formation and metastasis. Analogous mechanisms for cytokinesis failure may lead to polyploid intermediates in tumorigenesis in mammalian cancer models.

Highlights d LDH upregulation is required for the transition from hyperplasia to neoplasia d LDH expression drives tumor formation in the context of EGFR overexpression d Increased sugar uptake drives tumor formation in the Drosophila EGFR model d Synergy between EGFR and LDHA correlates with poor outcome in human cancer

Cytokinesis failure may result in the formation of polyploid cells, and subsequent mitosis can lead to aneuploidy and tumor formation. Tumor suppressor mechanisms limiting the oncogenic potential of these cells have been described. However, the universal applicability of these tumor-suppressive barriers remains controversial. Here, we use Drosophila epithelial cells to investigate the consequences of cytokinesis failure in vivo. We report that cleavage defects trigger the activation of the JNK pathway, leading to downregulation of the inhibitor of apoptosis DIAP1 and programmed cell death. Yorkie overcomes the tumor-suppressive role of JNK and induces neoplasia. Yorkie regulates the cell cycle phosphatase Cdc25/string, which drives tumorigenesis in a context of cytokinesis failure. These results highlight the functional significance of the JNK pathway in epithelial cells with defective cytokinesis and elucidate a mechanism used by emerging tumor cells to bypass this tumor-suppressive barrier and develop into tumors.

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Tissue growth has to be carefully controlled to generate well-functioning organs. MicroRNAs are small non-coding RNAs that modulate the activity of target genes and play a pivotal role in animal development. Understanding the functions of microRNAs in development requires the identification of their target genes. Here, we find that , a conserved microRNA in the family, controls tissue growth and homeostasis in the wing imaginal disc. Upregulation of causes the repression of , the effector of the Hippo pathway in, and reduces tissue size. Remarkably, co-expression of and causes the formation of neoplastic tumors. We show that upregulation of represses the growth inhibitor, and depletion of cooperates with in the formation of neoplastic tumors. Hence, modulates a positive growth regulator,, and a negative growth regulator, Deregulation of this network can result in the loss of tissue homeostasis and the formation of tumors.