Src controls tumorigenesis through JNK-dependent regulation of the Hippo pathway. Masato Enomoto¹, Tatsushi Igaki^1,2. 1) Division of Genetics, Kobe University Graduate School of Medicine, Kobe, Japan; 2) PRESTO, Japan Science and Technology Agency (JST), Saitama, Japan.

   Cell-cell interactions within the tumor microenvironment play crucial roles in epithelial tumorigenesis. However, the mechanism by which each genetic alteration contributes to oncogenic cell-cell communication is poorly understood. Here, we show that the oncoprotein Src regulates tumor microenvironment by JNK-dependent regulation of the Hippo pathway. Clones of cells with elevated Src expression activate the Rac-Diaphanous (Dia) and Ras-MAPK pathways, which cooperate to cause intracellular accumulation of F-actin, thereby leading to activation of the Hippo pathway effector Yorkie (Yki). Simultaneously, Src activates the JNK pathway, which antagonizes the autonomous Yki activity and causes propagation of Yki activity to neighboring cells, thereby inducing overgrowth of surrounding tissue. Blocking JNK signaling in Src-expressing clones cancels the propagation of Yki activity and leads to autonomous tumor overgrowth. Our findings unveil a mechanism of Src-induced tumorigenesis through JNK-dependent switch of Yki activity and would help understand how oncogene Src regulates tumor microenvironment in vivo.