During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis.

Background The American College of Cardiology Core Cardiovascular Training Statement (COCATS) defined echocardiography core competencies and set the minimum recommend number of echocardiograms to perform (150) and interpret (300) for independent practice in echocardiography (level 2 training). Fellows may lack exposure to key pathologies that are relatively infrequent, however, even when achieving an adequate number of studies performed and interpreted. We hypothesized that cardiology fellows would lack exposure to 1 or more cardiac pathologies related to core competencies in COCATS when performing and interpreting the minimum recommend number of studies for level 2 training. Methods We retrospectively reviewed 11,250 reports from consecutive echocardiograms interpreted (7,500) and performed (3,750) by 25 cardiology fellows at a University tertiary referral hospital who graduated between 2015 and 2019. The first 300 echocardiograms interpreted and the first 150 echocardiograms performed by each fellow were included in the analysis. Echocardiography reports were reviewed for cardiac pathologies relating to core competencies defined in COCATS. Results All 25 fellows lacked exposure to 1 or more cardiac pathologies related to echocardiography core competencies despite meeting COCATS minimum recommended numbers for echocardiograms performed and interpreted. Pathologies for which 1 or more fellows encountered 0 cases despite meeting the minimum recommended numbers for both echocardiograms performed and interpreted included: pericardial constriction (16/25 fellows), aortic dissection (15/25 fellows), pericardial tamponade (4/25 fellows), valvular mass/thrombus (2/25 fellows), prosthetic valve dysfunction (1/25 fellows), and cardiac chamber mass/thrombus (1/25 fellows). Conclusions Cardiology fellows who completed the minimum recommend number of echocardiograms performed and interpreted for COCATS level 2 training frequently lacked exposure to cardiac pathologies, even in a University tertiary referral hospital setting. These data suggest that fellowship programs should monitor pathology case counts for each fellow in training, in addition to the minimum recommend number of echocardiograms defined by COCATS, to ensure competency for independent practice in echocardiography.

Bierowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Highlights We present an isolated skull metastasis in stage IB2 squamous cell carcinoma of the cervix. Providers should have high index of suspicion for skull mass following cervical carcinoma diagnosis. Adding denosumab to treatment regimen for bony metastasis should be considered due to its bone stabilizing properties.