Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence
Although activating mutations in the GTPase Ras promote cancer, Ras also induces cellular senescence, a barrier that is necessary to overcome for Ras activation to promote tumor progression. Using a model of Ras-induced tumor growth in flies, Ito and Igaki found that Ras-induced cellular senescence required the ETS family transcription factor Pnt. Loss of cell polarity, which frequently occurs in cancers of epithelial origin, activated the transcription factor Yki, resulting in a series of microRNA-mediated regulatory events that ultimately inhibited Pnt. Given the conservation of most of these proteins and their regulatory relationships, this mechanism may be relevant to how the loss of cell polarity removes the brakes on Ras-induced tumor growth in humans.
The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam. bantam-mediated repression of the E3 ligase–associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.