A feed-forward loop between Toll/NF-κB and Rac1 promotes Epithelial to Mesenchymal Transition of Ras-oncogenic hindgut enterocytes in Drosophila

Cancer cell invasion and subsequent metastasis accounts for most cancer related deaths. However, despite recent progress, there is a need to understand how the main pathways involved in oncogenic cell invasion and metastasis amalgamate into multifunctional networks. Using functional transcriptomic analysis of Drosophila Ras oncogenic hindgut enterocytes, we identified a feed-forward loop between the Toll/NF-κB innate immune pathway and Rac1 signaling driving actin cytoskeleton rearrangements, basement membrane degradation, and loss of intercellular adhesion. We find that this network is necessary and sufficient to promote oncogenic hindgut enterocyte invasion and dissemination. The network is orchestrated by Rac1, which promotes actin cytoskeleton alterations, JNK-mediated matrix metalloprotease-mediated basement membrane degradation and Toll-Snail-depended E-cadherin repression, leading to epithelial-to- mesenchymal transition and dissemination. However, Toll pathway positively regulates itself and the Rac1 pathway cytoskeletal genes downstream of the Ras oncogene, while JNK signaling alone does not suffice to induce cell dissemination. The tight crosstalk between Toll and Rac1 pathways reveals an integral role of Toll/NF-κB in Ras-initiated oncogenic epithelial cell migration. Comparative Gene expression analysis of RNA-Seq data between RasV12 expressing and control Drosophila hindguts