Abstract
The Hippo pathway is classically viewed as a tumor suppressor that limits tissue growth by inhibiting the transcriptional co-activator Yorkie/YAP. Accordingly, Hippo activation is expected to suppress proliferation and can promote apoptosis. In this issue, Honda and colleagues challenge the prevailing unidirectional view of Hippo signaling as a purely tumor-suppressive pathway by showing that the outcome of Hippo activation is highly context-dependent in the Drosophila wing disc (Honda et al, 2026). In the wing pouch, Hippo activation leads primarily to growth suppression, as expected. In contrast, in the hinge and ventral notum, Hippo-activated cells survive and act as “oncogenic niche” cells that stimulate tumorigenic proliferation in neighboring cells. This tumor-promoting effect is mediated by non-apoptotic activity of the initiator caspase Dronc, induction of Wnt and EGF signaling, and metabolic support provided by the amino-acid transporters Sat1 and Sat2, which together drive mTOR activation in nearby cells. These findings reveal how growth suppression in one cell population can paradoxically drive tumor growth in another, reframing Hippo activity as a regulator of tumor-promoting microenvironments.
