THE YKI-CACTUS (I_KBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA

Abstract

Presence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved in Drosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We used Drosophila tumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms of Ras[V12] or its major effector Yorkie (Yki[3SA]) in polarity deficient cells mutant for tumor suppressor gene scribble (scrib) marked by GFP under nubGAL4 or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth of Yki[3SA] scrib[RNAi] or Ras[V12] scrib[RNAi] tumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated in Yki[3SA]scrib[RNAi] or Ras[V12]scrib[RNAi] tumors. Drosophila Cactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.