Hungry for Mechanism in Hippo Signaling

Ras activation and mitochondrial dysfunction (green) stimulate cell proliferation (magenta) of surrounding cells (blue). Image courtesy of Tatsushi Igaki. Inhibiting Hippo Helps Neighbors Grow Cell-autonomous growth control has been extensively studied in cancer; however, the mechanisms through which cancer cells influence their neighbors’ growth are poorly understood. A new study by Ohsawa et al. finds that Hippo signaling is an integral component of a nonautonomous pathway for proliferation and invasion that is driven by oncogenic Ras and oxidative stress. Using a fly eye overgrowth model, Ohsawa et al. surprisingly find that mutations in mitochondrial genes can cooperate with Ras to drive proliferation in adjacent cells. Ras and mitochondrial dysfunction together cause oxidative stress, which suppresses Hippo signaling and activates the downstream transcriptional coactivator, Yorkie (YAP in humans). Yorkie upregulates Wingless (a Wnt homolog) and Unpaired (a JAK/STAT ligand), which drive proliferation and invasion in nearby cells that have active Ras but normal mitochondrial function. Interestingly, no overgrowth is seen in the Ras-active and mitochondriadefective cells themselves, perhaps due to mitochondrial dysfunctioninduced cell-cycle arrest. These results provide a potential mechanism of cooperativity within genetically heterogeneous tumors. Furthermore, they position the Hippo pathway as an important mediator for this effect. Whether this mechanism is involved in cancer development remains to be seen; however, the high incidence of both Ras mutation and mitochondrial dysfunction in many types of cancer make this a promising finding. Ohsawa, S., et al. (2012). Nature 490, 547–551.