α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5β1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP–α5β1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo

α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

[Abstract]: Adaptive and fluid applications development methodologies such as Prototyping, RAD, FAD and Ex-treme Programming have emerged in recent years in response to organisational realities that include rapid change, uncertainty and ambiguity. These methodologies are well suited to the team-based approach that has become so important in the modern organisation. Yet, many educational programmes in the West still focus on individual learning and assessment. This paper reports on a pilot study where team-based methods are incorporated into a demanding undergraduate I.T. course. An attempt is also made to create a learning environment that incorporates elements of the ‘real world.’ It is established that a team-based approach, where there is a focus on interdependency and group learning, can lead to some dramatic improvements in the performance of IT students but a number of unexpected problems emerge