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 account 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 identify a feed-forward loop between the archetypical Toll/NF-κB pathway and Rac1 signalling driving actin cytoskeleton rearrangements, basement membrane degradation, and loss of intercellular adhesion. Our data support a signalling network in which Rac1, Toll and JNK signalling transmit the RasV12 signal that primes the hindgut enterocytes towards delamination and dissemination. Rac1 induces actin cytoskeleton signalling genes, Rok, sqh, Apr2, and Apr3, while JNK induces matrix metalloprotease-mediated basement membrane degradation and Toll induces snail-depended E-cadherin repression. Moreover, the Toll pathway positively regulates itself and the Rac1 pathway cytoskeletal genes downstream of the Ras oncogene, but JNK signalling alone does not suffice to induce cell dissemination. Notably, there is a tight crosstalk between Toll and Rac1 signalling that suffices to induce hindgut enterocyte invasiveness and has the key role in transmitting the RasV12 signal.