Oncogenic Ras-driven Dorsal/NF-κB signaling contributes to tumorigenesis in aDrosophilacarcinoma model

Abstract

AbstractCancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis.Drosophila melanogastertumour models are increasingly recognized as models to inform conserved molecular mechanisms of tumorigenesis with both local and systemic effects of cancer. Although initial discoveries of the Toll-NFκB signaling pathway in development and immunity was pioneered inDrosophila, limited information is available for its role in cancer progression. Using a well-studied cooperative RasV12-driven epithelial-derived tumour model, we here describe functions of Toll-NF-κB signaling in malignantRasV12, scrib-tumors. The extracellular Toll pathway components ModSP and PGRP-SA and intracellular signaling Kinase, Pelle/IRAK, are rate-limiting for tumor growth. The Toll pathway NFκB protein Dorsal, as well ascactus/IκB show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic RasV12, and not loss ofscribble,confers increased expression and heterogenous distribution of two Dorsal isoforms, DorsalA and DorsalB in different tumour cell populations. Mechanistic analyses demonstrates that Dorsal drives growth and malignancy by suppressing differentiation, counteracting apoptosis and promoting invasion ofRasV12, scrib-tumors genetically dependent ontwistandsnail.