Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia

ABSTRACT Out-of-context gain of nuclear signaling of mammalian YAP/TAZ or Drosophila Yki—the transcription cofactors of the highly conserved Hippo tumor suppressor pathway—is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs of Drosophila . Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2—a Drosophila homolog of mammalian IGFBP7—without arresting tumor progression per se . By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs in Drosophila by arresting runaway PI3K/Akt/TOR signaling.