Significance: Cancer is the leading cause of death worldwide, although studies revealed that dysregulation of the Hippo pathway contributes to tumorigenesis, whereas its roles in tumor invasion and cell migration remain paradoxical and largely elusive. Using Drosophila as a model, we herein find cross-talk between the Hippo and JNK pathways in regulating cell migration and invasion. Mechanistically, we identify bantam -Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Our finding is particularly important as it offers a wake-up call for therapeutic interventions of Hippo-related cancers, because simply increasing Hippo signal activity may paradoxically accelerate cell invasion and metastasis.

The Notch signaling pathway controls cell growth, differentiation, and fate decisions, and its dysregulation has been linked to various human genetic disorders and cancers. To comprehensively understand the global organization of the Notch pathway and identify potential drug targets for Notch-related diseases, we established a protein interaction landscape for the human Notch pathway. By combining and analyzing genetic and phenotypic data with bioinformatics analysis, we greatly expanded this pathway and identified many key regulators, including low-density-lipoprotein-receptor-related protein 1 (LRP1). We demonstrated that LRP1 mediates the ubiquitination chain linkage switching of Delta ligands, which further affects ligand recycling, membrane localization, and stability. LRP1 inhibition led to Notch signaling inhibition and decreased tumorigenesis in leukemia models. Our study provides a glimpse into the Notch pathway interaction network and uncovers LRP1 as one critical regulator of the Notch pathway, as well as a possible therapeutic target for Notch-related cancers.

RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed, partly because of an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (RasV12) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with RasV12 to drive c-Jun N-terminal kinase (JNK)-dependent tumor growth and invasiveness. We show that Fmt negatively regulates JNK upstream of dTAK1. We further demonstrate that disruption of PpV, the catalytic subunit of PP6, mimics fmt loss-of-function-induced tumorigenesis. Finally, Fmt synergizes with PpV to inhibit JNK-dependent tumor progression. Our data here further highlight the power of Drosophila as a model system to unravel molecular mechanisms that may be relevant to human cancer biology.

Significance: Both Hippo and c-Jun N-terminal kinase (JNK) signaling have well-established roles in promoting tissue growth, while it remains elusive whether and how the two pathways interact or coordinate in growth control. We report in the present study that the Hpo–Yki pathway modulates Rho1–JNK signaling-mediated growth in Drosophila wing development. We show that the impaired Hpo pathway activates JNK through transcriptional up-regulation of Rho1. These findings expands our understanding about the cross-talk between two important signaling pathways, namely Hippo–Yki and Rho1–JNK, in regulating growth.