Oncogenic Ras-driven Dorsal/NF-κB signaling contributes to tumorigenesis in a Drosophila carcinoma model

Cancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis. Drosophila melanogaster tumour 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 in Drosophila , limited information is available for its role in cancer progression. Using a well-studied cooperative Ras ^V12 -driven epithelial-derived tumour model, we here describe functions of Toll-NF-κB signaling in malignant Ras ^V12 , 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 as cactus/I κB show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic Ras ^V12 , and not loss of scribble, 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 of Ras ^V12 , scrib ^- tumors genetically dependent on twist and snail .