Hippo-TOR Signaling Crosstalks Underpin Microtubule Acetylation-linked Carcinogenesis inDrosophilaSquamous Epithelia

ABSTRACT Flattened squamous epithelial tissues undergo extensive cytoskeletal remodeling and display perpetual nuclear signaling of the Hippo transcription cofactor, YAP/TAZ, in mammals and Yki in Drosophila . Loss of YAP in humans or Yki in Drosophila causes squamous cell carcinoma (SCC), but only in select cell types. Here, we reveal a mechanism of Yki-loss induced SCC in the lumen-lining squamous epithelium of the male accessory gland (MAG) in Drosophila . Yki loss in the MAG triggers TOR signaling-mediated microtubule hyperacetylation, which causally underpins its SCC. By contrast, Yki loss in the oocyte-enveloping follicular squamous epithelium neither activates TOR nor induce microtubule hyperacetylation. Analysis of available single-cell transcriptomic data further revealed characteristic MAG and follicular squamous cell type-specific signatures of Yki and TOR signaling. Thus, the disparate epigenetic landscapes and distinct mechanosensory cues likely prefigures their susceptibility to Yki-loss, with lumen-lining squamous epithelia being oncogenically more susceptible.