Autocrine IL-1β-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFα signalling to carcinoma-associated fibroblasts

The invasion of Squamous Cell Carcinoma (SCC) is a significant cause of morbidity and mortality. Here we identify an E3 ligase, Traf6, and a de-ubiquitinating enzyme, Cezanne/ZA20D1, as important regulators of this process in organotypic models. Traf6 can promote the formation of Cdc42-dependent F-actin microspikes. Furthermore, Traf6 plays a key role in autocrine Interleukin-1β signalling in SCC cells which in turn is required to drive the expression of Tumour Necrosis Factor α (TNFα). TNFα acts in a paracrine manner to increase the invasion promoting potential of carcinoma-associated fibroblasts. Exogenous TNFα signalling can restore invasion in cells depleted of Traf6. In conclusion, Traf6 plays two important roles in SCC invasion: it promotes cell intrinsic Cdc42-dependent regulation of the actin cytoskeleton and enables production of the paracrine signal, TNFα, that enhances the activity of carcinoma-associated fibroblasts.