Loss of canonical sex steroid signaling correlates with prostate cancer progression and induces tumor escape in Drosophila

In cancer, tumor escape often arises following treatments. This is especially true during deprivation therapies, where this phenomenon has been linked to steroid signaling reactivation despite deprivation. Here, we show that in prostate cancer tissues the canonical androgen pathway itself is deactivated and, in fact, loss of canonical AR signaling tightly correlates with cancer progression. This raises the possibility that loss of canonical sex steroid signaling could promote the progression. We tested this hypothesis a drosophila model of prostate cancer. There, repression of canonical sex steroid ecdysone receptor signaling displays both anti- and protumor effects. On the one hand, it slightly decreases extra-epithelial tumor formation, and increases their propensity for apoptosis. On the other hand, it induces the growth of a new tumor cell population, which growth is normally prevented by autocrine/intracrine ecdysone signaling. Furthermore, this population appears to emerge from epithelial clones within the gland. To do so, tumor cells change the way they migrate out of the epithelium, forming a new layer between the normal epithelium and the basement membrane. This depends on a modification of epithelial basal extrusion that likely relies on the downregulation of Ecdysone target gene Tub60D. Thus, in drosophila accessory gland, lack of sex steroid signaling not only coincides with but actually induces tumor escape. Together, these results question the role of sex steroid deprivation on tumor progression, and point to altered basal extrusion as a possible mechanism shaping tumor escape.