HMENA is a key regulator in endothelin-1/\u3b2-arrestin1- induced invadopodial function and metastatic process

Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by \u3b2-arrestin1 (\u3b2-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of \u3b2-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENA\u3b4v6 isoforms through \u3b2-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of \u3b2-arr1 with hMENA/hMENA\u3b4v6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of \u3b2-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/\u3b2-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENA\u3b4v6 for ET-1/ \u3b2-arr1-induced invadopodial activity and ovarian cancer progression

The pattern of hMENA isoforms is regulated by TGF-\u3b21 in pancreatic cancer and may predict patient outcome

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA(11a), and hMENA\u394v6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA(11a) antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA(11a) isoform only showed strong staining in 26% of PDAC. The absence of hMENA(11a) in a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-\u3b21-treated PDAC cell lines. hMENA(11a) knock-down in PDAC cell lines affected cell-cell adhesion but not invasion. TGF-\u3b21 cooperated with \u3b2-catenin signaling to upregulate hMENA and hMENA\u394v6 expression but not hMENA(11a) In the absence of hMENA(11a), the hMENA/hMENA\u394v6 up-regulation is crucial for SMAD2-mediated TGF-\u3b21 signaling and TGF-\u3b21-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC

The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation

The dynamic interplay between cancer cells and cancer-associated fibroblasts (CAFs) is regulated by multiple signaling pathways, which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin regulatory protein of Ena/VASP family, and its tissue-specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENA\u394v6 isoforms in tumor-promoting CAFs and in the modulation of pro-tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation. LC-MS/MS proteomic analysis reveals that CAFs that overexpress hMENA\u394v6 secrete the AXL ligand GAS6, favoring the invasiveness of AXL-expressing pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) cells. Reciprocally, hMENA/hMENA\u394v6 regulates AXL expression in tumor cells, thus sustaining GAS6-AXL axis, reported as crucial in EMT, immune evasion, and drug resistance. Clinically, we found that a high hMENA/GAS6/AXL gene expression signature is associated with a poor prognosis in PDAC and NSCLC. We propose that hMENA contributes to cancer progression through paracrine tumor-stroma crosstalk, with far-reaching prognostic and therapeutic implications for NSCLC and PDAC

Exploring the Solar Wind from Its Source on the Corona into the Inner Heliosphere during the First Solar Orbiter\u2013Parker Solar Probe Quadrature

This Letter addresses the first Solar Orbiter (SO)-Parker Solar Probe (PSP) quadrature, occurring on 2021 January 18 to investigate the evolution of solar wind from the extended corona to the inner heliosphere. Assuming ballistic propagation, the same plasma volume observed remotely in the corona at altitudes between 3.5 and 6.3 solar radii above the solar limb with the Metis coronagraph on SO can be tracked to PSP, orbiting at 0.1 au, thus allowing the local properties of the solar wind to be linked to the coronal source region from where it originated. Thanks to the close approach of PSP to the Sun and the simultaneous Metis observation of the solar corona, the flow-aligned magnetic field and the bulk kinetic energy flux density can be empirically inferred along the coronal current sheet with an unprecedented accuracy, allowing in particular estimation of the Alfven radius at 8.7 solar radii during the time of this event. This is thus the very first study of the same solar wind plasma as it expands from the sub-Alfvenic solar corona to just above the Alfven surface