A feed-forward loop between Toll/NF-κB and Rac1 promotes epithelial to mesenchymal transition of Ras-oncogenic hindgut enterocytes in Drosophila

TL;DR

The study reveals how cancer cell invasion is driven by a signaling loop involving Toll/NF-κB and Rac1 in fruit fly gut cells.

Contribution

A novel feed-forward loop between Toll/NF-κB and Rac1 signaling is identified in promoting cell invasion in Drosophila.

Findings

A feed-forward loop between Toll/NF-κB and Rac1 drives epithelial to mesenchymal transition in Ras-oncogenic hindgut enterocytes.

Toll and Rac1 signaling coordinate cytoskeletal changes, adhesion loss, and basement membrane degradation.

JNK signaling alone is insufficient for cell dissemination, but Toll-Rac1 crosstalk is key.

Abstract

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.

Summary: A feed-forward loop between Toll/NF-κB and Rac1 signalling drives Ras-induced cell invasion by coordinating cytoskeletal changes, adhesion loss, and basement membrane degradation in Drosophila hindgut enterocytes.

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