Trop-2 is a universal cancer growth stimulator through a ubiquitous signaling platform

Trop-2 is a transmembrane calcium signal transducer. Our findings show that Trop-2 is overexpressed by the majority of human cancers, suggesting strong selective pressure for a conserved function. Trop-2 was then demonstrated to be necessary and sufficient to stimulate cancer growth, with a linear relationship between growth rates and Trop-2 expression levels. Cell growth stimulation was shown to be conserved across cell-types and species. These findings indicated impingement on a ubiquitous downstream signal-transduction module. The Trop-2 signaling pathway was investigated by yeast 2 hybrid screening, coimmunoprecipitation / massspectrometry and proteomic chip analysis. Trop-2 was demonstrated to bind CD44 and tetraspanins, triggering their growth-promoting ability via a feed-forward activation loop of CD9-recruited PKCα and phosphorylation of the Trop-2 cytoplasmic tail. We demonstrate that PKCα stimulates growth in a Trop-2-restricted manner and that PKCα and Trop-2 are coordinately transported in recurrent waves to membrane ruffles and podosomes. Trop-2 induction was shown to activate the ERK pathway, to up-regulate NF-κB, and to modulate apoptotic factors, including p53 and Rb. Members of the Trop-2 pathway (CD9, CD44 and p53) were found coordinately upregulated in retrospective studies of human cancer case series. These findings reveal the existence of a novel, strikingly widespread mechanism of stimulation of cancer growth. This is quantitatively driven by a wild-type Trop-2 and acts upon ready-to-signal, ubiquitous signal-transduction platforms.