BackgroundCell migration is essential for development and tissue repair, but it also contributes to disease. Rho GTPases regulate cell migration, but a comprehensive analysis of how each Rho signalling component affects migration has not been carried out.ResultsThrough an RNA interference screen, and using a prostate cancer cell line, we find that approximately 25% of Rho network components alter migration. Some genes enhance migration while others decrease basal and/or hepatocyte growth factor-stimulated migration. Surprisingly, we identify RhoH as a screen hit. RhoH expression is normally restricted to haematopoietic cells, but we find it is expressed in multiple epithelial cancer cell lines. High RhoH expression in samples from prostate cancer patients correlates with earlier relapse. RhoH depletion reduces cell speed and persistence and decreases migratory polarity. Rac1 activity normally localizes to the front of migrating cells at areas of dynamic membrane movement, but in RhoH-depleted cells active Rac1 is localised around the whole cell periphery and associated with membrane regions that are not extending or retracting. RhoH interacts with Rac1 and with several p21-activated kinases (PAKs), which are Rac effectors. Similar to RhoH depletion, PAK2 depletion increases cell spread area and reduces cell migration. In addition, RhoH depletion reduces lamellipodium extension induced by PAK2 overexpression.ConclusionsWe describe a novel role for RhoH in prostate cancer cell migration. We propose that RhoH promotes cell migration by coupling Rac1 activity and PAK2 to membrane protrusion. Our results also suggest that RhoH expression levels correlate with prostate cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0489-4) contains supplementary material, which is available to authorized users.

The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and regulate epithelial mesenchymal transition (EMT), however the potential role of CAR in lung cancer metastasis remains poorly understood. To better understand the role of this receptor in tumor progression, we manipulated CAR expression in both epithelial-like and mesenchymal-like lung cancer cells. In both cases, CAR overexpression promoted tumor growth in vivo in immunocompetent mice and increased cell adhesion in the lung after intravenous injection without altering the EMT properties of each cell line. Overexpression of WTCAR resulted in increased invasion in 3D models and enhanced β1 integrin activity in both cell lines, and this was dependent on phosphorylation of the CAR cytoplasmic tail. Furthermore, phosphorylation of CAR was enhanced by substrate stiffness in vitro, and CAR expression increased at the boundary of solid tumors in vivo. Moreover, CAR formed a complex with the focal adhesion proteins Src, Focal Adhesion Kinase (FAK) and paxillin and promoted activation of the Guanine Triphosphate (GTP)-ase Ras-related Protein 1 (Rap1), which in turn mediated enhanced integrin activation. Taken together, our data demonstrate that CAR contributes to lung cancer metastasis via promotion of cell-matrix adhesion, providing new insight into co-operation between cell-cell and cell-matrix proteins that regulate different steps of tumorigenesis.

Coxsackievirus and adenovirus receptor (CAR) is a transmembrane cell–cell adhesion receptor that forms homodimers across junctions and plays a key role in mediating epithelial barrier integrity. CAR can also heterodimerise with receptors on the surface of leukocytes and thus plays an additional role in mediating immune cell transmigration across epithelial tissues. Given the importance of both biological processes in cancer, CAR is emerging as a potential mediator of tumorigenesis as well as a target on cancer cells for viral therapy delivery. However, the emerging, often conflicting, evidence suggests that CAR function is tightly regulated and that contributions to disease progression are likely to be context specific. Here, we summarise reported roles for CAR in the context of cancer and draw on observations in other disease settings to offer a perspective on the potential relevance of this receptor as a therapeutic target for solid tumours.

Digitalization produces increasingly multimodal and interactive literary forms. A major challenge for foreign language education in adopting such forms lies in deconstructing discursive borders between literary education and digital education (romance of the book vs. euphoric media heavens), thereby crossing over into a perspective in which digital and literary education are intertwined. In engaging with digital literary texts, it is additionally important to consider how different competencies and literary/literacy practices interact and inform each other, including: (1) a receptive perspective: reading digital narratives and digital literature can become a space for literary aesthetic experience, and (2) a productive perspective: learners can become “produsers” (Bruns, 2008) of their own digital narratives by drawing on existing genre conventions and redesigning “available designs” (New London Group, 1996). Consequently, we propose a typology of digital literatures, incorporating functional, interactive and narrative aspects, as applied to a diverse range of digital texts. To further support our discussion, we draw on a range of international studies in the fields of literacies education and 21st century literatures (e.g., Beavis, 2010; Hammond, 2016; Kalantzis & Cope, 2012; Ryan, 2015) and, in turn, explore trajectories for using concrete digital literary texts in the foreign language classroom.

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