Living cells and the extracellular matrix (ECM) can display complex interactions that define key developmental, physiological and pathological processes. Here, we report a new type of directed migration — which we term ‘topotaxis’ — by which cell movement is guided by the gradient of the nanoscale topographic features in the cells’ ECM environment. We show that the direction of topotaxis is reflective of the effective cell stiffness, and that it depends on the balance of the ECM-triggered signalling pathways PI3K-Akt and ROCK-MLCK. In melanoma cancer cells, this balance can be altered by different ECM inputs, pharmacological perturbations or genetic alterations, particularly a loss of PTEN in aggressive melanoma cells. We conclude that topotaxis is a product of the material properties of cells and the surrounding ECM, and propose that the invasive capacity of many cancers may depend broadly on topotactic responses, providing a potentially attractive mechanism for controlling invasive and metastatic behaviour.

Collective cell migration occurs in many patho-physiological states, including wound healing and invasive cancer growth. The integrity of the expanding epithelial sheets depends on extracellular cues, including cell-cell and cell-matrix interactions. We show that the nano-scale topography of the extracellular matrix underlying epithelial cell layers can strongly affect the speed and morphology of the fronts of the expanding sheet, triggering partial and complete epithelial-mesenchymal transitions (EMTs). We further demonstrate that this behavior depends on the mechano-sensitivity of the transcription regulator YAP and two new YAP-mediated cross-regulating feedback mechanisms: Wilms Tumor-1-YAP-mediated downregulation of E-cadherin, loosening cell-cell contacts, and YAP-TRIO-Merlin mediated regulation of Rho GTPase family proteins, enhancing cell migration. These YAP-dependent feedback loops result in a switch-like change in the signaling and the expression of EMT-related markers, leading to a robust enhancement in invasive cell spread, which may lead to a worsened clinical outcome in renal and other cancers.

Transforming growth factor-β (TGF-β) is a potent anti-inflammatory cytokine that regulates interleukin-1 receptor and Toll-like receptor (TLR) signalling. Here we show a novel mechanism where TGF-β1-induced K48-linked polyubiquitination and degradation of the adaptor myD88 protein is dependent on the smad6 protein, but not smad7, and mediated by recruitment of the smad ubiquitin regulator factor proteins, smurf1 and smurf2, which have E3-ubiquitin ligase activity. smurf1 interaction with myD88 appears to be mediated by smad6, and smurf2 interaction by smurf1. Knockdown of endogenous smurf1 or smurf2 by RnA interference significantly suppresses the anti-inflammatory effects of TGF-β1 by preventing lipopolysaccharide-induced nF-κB nuclear translocation, resulting in de-suppression of proinflammatory gene expression. similar effects are observed on the lipoteichoic-acid-induced TLR2 pathway, which is also myD88-dependent, but not the myD88-independent TLR3 pathway. Thus, our results suggest that myD88 degradation driven by the smad6-smurf pathway is a novel mechanism for TGF-β1-mediated negative regulation of myD88-dependent pro-inflammatory signalling.