Semaphorin signaling in cancer cells and in cells of the tumor microenvironment – two sides of a coin

Semaphorins are a large family of secreted and membrane-bound molecules that were initially implicated in the development of the nervous system and in axon guidance. More recently, they have been found to regulate cell adhesion and motility, angiogenesis, immune responses, and tumor progression. Semaphorin receptors, the neuropilins and the plexins, are expressed by a wide variety of cell types, including endothelial cells, bone-marrow-derived cells and cancer cells. Interestingly, a growing body of evidence indicates that semaphorins also have an important role in cancer. It is now known that cancer progression, invasion and metastasis involve not only genetic changes in the tumor cells but also crosstalk between tumor cells and their surrounding non-tumor cells. Through the recruitment of endothelial cells, leukocytes, pericytes and fibroblasts, and the local release of growth factors and cytokines, the tumor microenvironment can mediate tumor-cell survival, tumor proliferation and regulation of the immune response. Moreover, by conferring cancer cells with an enhanced ability to migrate and invade adjacent tissues, extracellular regulatory signals can play a major role in the metastatic process. In this Commentary, we focus on the emerging role of semaphorins in mediating the crosstalk between tumor cells and multiple stromal cell types in the surrounding microenvironment

Le semaforine: segnali di guida neuro-vascolari che controllano la migrazione cellulare, l’angiogenesi, la progressione tumorale

Le semaforine sono una famiglia di molecole segnale conservata nell’evoluzione dagli invertebrati all’uomo. I recettori delle semaforine appartengono alle famiglie delle plexine e delle neuropiline. Le semaforine agiscono come segnali guida durante lo sviluppo del sistema nervoso, controllando il direzionamento assonico e la formazione della rete neurale. Esse controllano inoltre la migrazione di molteplici popolazioni cellulari durante lo sviluppo, tra cui le cellule della cresta neurale e le cellule endoteliali. La rilevanza del ruolo di controllo di questi segnali è evidente dal fatto che – in loro assenza – si verificano importanti difetti di sviluppo embrionale, talvolta letali, come ad esempio quando colpiscono il sistema cardiovascolare. Due delle semaforine che abbiamo studiato, Sema3A e Sema3E, hanno appunto un ruolo importante nell’angiogenesi embrionale. In particolare, nel caso della Sema3E, noi ed altri abbiamo descritto diverse vie di segnalazione attive in cellule endoteliali, attraverso il recettore PlexinaD1, che possono spiegare la funzione regolatoria sull’angiogenesi. Abbiamo quindi dimostrato che il ruolo regolatorio di Sema3A e Sema3E si estende anche alla neo-angiogenesi che si osserva nell’adulto, a livello del tessuto tumorale. In particolare, le cellule neoplastiche rilasciano entrambe le semaforine e il loro livello di espressione condiziona la possibilità di sviluppare un sistema vascolare adeguato e quindi la capacità di accrescimento del tumore in vivo. La Sema3E è infine una molecola interessante perché è in grado di attivare risposte biologiche distinte in popolazioni cellulari diverse. Ad esempio, in cellule tumorali umane essa non induce il tipico effetto repulsivo/inibitorio, ma invece attiva la formazione di invadopodi e la capacita’ invasiva/metastatica, attraverso una via di segnalazione specifica

p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling

Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins

Polariton Nanophotonics using Phase Change Materials

Polaritons formed by the coupling of light and material excitations such as plasmons, phonons, or excitons enable light-matter interactions at the nanoscale beyond what is currently possible with conventional optics. Recently, significant interest has been attracted by polaritons in van der Waals materials, which could lead to applications in sensing, integrated photonic circuits and detectors. However, novel techniques are required to control the propagation of polaritons at the nanoscale and to implement the first practical devices. Here we report the experimental realization of polariton refractive and meta-optics in the mid-infrared by exploiting the properties of low-loss phonon polaritons in isotopically pure hexagonal boron nitride (hBN), which allow it to interact with the surrounding dielectric environment comprising the low-loss phase change material, Ge$_3$Sb$_2$Te$_6$ (GST). We demonstrate waveguides which confine polaritons in a 1D geometry, and refractive optical elements such as lenses and prisms for phonon polaritons in hBN, which we characterize using scanning near field optical microscopy. Furthermore, we demonstrate metalenses, which allow for polariton wavefront engineering and sub-wavelength focusing. Our method, due to its sub-diffraction and planar nature, will enable the realization of programmable miniaturized integrated optoelectronic devices, and will lay the foundation for on-demand biosensors.Comment: 15 pages, 4 figures, typos corrected in v

Plexin A Is a Neuronal Semaphorin Receptor that Controls Axon Guidance

AbstractThe Semaphorins comprise a large family of secreted and transmembrane proteins, some of which function as repellents during axon guidance. Semaphorins fall into seven subclasses. Neuropilins are neuronal receptors for class III Semaphorins. In the immune system, VESPR, a member of the Plexin family, is a receptor for a viral-encoded Semaphorin. Here, we identify two Drosophila Plexins, both of which are expressed in the developing nervous system. We present evidence that Plexin A is a neuronal receptor for class I Semaphorins (Sema 1a and Sema 1b) and show that Plexin A controls motor and CNS axon guidance. Plexins, which themselves contain complete Semaphorin domains, may be both the ancestors of classical Semaphorins and binding partners for Semaphorins