NF-kB signaling driven by oncogenic Ras 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-NFkB 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 RasV12 -driven epithelial-derived tumour model, we here describe functions of Toll- NF-kB signaling in malignant RasV12, 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 NFkB protein Dorsal, as well as cactus/IkB show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic RasV12, 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, in concert with the BTB-transcription factor Chinmo, drives growth and malignancy by suppressing differentiation, counteracting apoptosis and promoting invasion of RasV12, scrib- tumors. RNASeq profiling of FACS sorted cells from day 6 eye-antennal discs with Gmr-GFP (control) GFP+ (RasV12, scrib-/-) tumor cells and GFP- tumor microenvironment cells from tumor carrying discs.