Strategic trastuzumab mediated crosslinking driving concomitant HER2 and HER3 endocytosis and degradation in breast cancer

Efficacious anticancer therapies for targeting plasma membrane receptors with antibody based therapeutics are often contingent on sufficient endocytic delivery of receptor and conjugate to lysosomes. This results in downregulation of receptor activity and, in the case of antibody-drug conjugates (ADCs), intracellular release of a drug payload. The oncogenic receptor HER2 is a priority therapeutic target in breast cancer. Known as an “endocytosis resistant” receptor, HER2 thwarts the receptor downregulating efficiency of the frontline treatment trastuzumab and reduces the potential of trastuzumab-based therapies such as trastuzumab-emtansine. We previously demonstrated that strategically inducing trastuzumab and HER2 crosslinking in breast cancer cells promoted endocytosis and lysosomal delivery of the HER2-trastuzumab complex, stimulating downregulation of the receptor. Here we reveal that HER3, but not EGFR, is also concomitantly downregulated with HER2 after crosslinking. This is accompanied by strong activation of MEK/ERK pathway that we show does not directly contribute to HER2/trastuzumab endocytosis. We show that crosslinking induced trastuzumab endocytosis occurs via clathrin-dependent and independent pathways and is an actin-dependent process. Detailed ultrastructural studies of the plasma membrane highlight crosslinking-specific remodelling of microvilli and induction of extensive ruffling. Investigations in a cell model of acquired trastuzumab resistance demonstrate, for the first time, that they are refractory to crosslinking induced HER2 endocytosis and downregulation. This implicates further arrest of HER2 internalisation in developing trastuzumab resistance. Overall our findings highlight the potential of receptor crosslinking as a therapeutic strategy for cancer while exposing the ability of cancer cells to develop resistance via endocytic mechanisms

The Effects of Beetroot Juice on Blood Pressure, Microvascular Function and Large-Vessel Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Pilot Study in Healthy Older Adults.

Dietary nitrate (NO ) has been reported to improve endothelial function (EF) and blood pressure (BP). However, most studies only assess large-vessel EF with little research on the microvasculature. Thus, the aim of the present pilot study is to examine NO supplementation on microvascular and large-vessel EF and BP. Twenty older adults (63 ± 6 years) were randomized to a beetroot juice (BRJ) or placebo (PLA) group for 28 (±7) days and attended three laboratory visitations. Across visitations, blood pressure, microvascular function and large-vessel EF were assessed by laser Doppler imaging (LDI) with iontophoresis of vasoactive substances and flow-mediated dilatation (FMD), respectively. Plasma NO concentrations, BP and the presence of NO reducing bacteria were also assessed. Plasma NO increased following two weeks of BRJ supplementation (p = 0.04) along with a concomitant decrease in systolic and diastolic BP of approximately −6 mmHg and −4 mmHg, respectively (p = 0.04; p = 0.01, respectively). BP remained unchanged in the PLA group. There were no significant differences in endothelium-dependent or endothelium-independent microvascular responses between groups. FMD increased by 1.5% following two weeks of BRJ (p = 0.04), with only a minimal (0.1%) change for the PLA group. In conclusion, this pilot study demonstrated that medium-term BRJ ingestion potentially improves SBP, DBP and large-vessel EF in healthy older adults. The improvements observed in the present study are likely to be greater in populations presenting with endothelial dysfunction. Thus, further prospective studies are warranted in individuals at greater risk for cardiovascular disease

Can gardeners identify ‘future invaders’?

It is estimated that there are 30 million gardeners in Britain, who could play a crucial role in being the ‘first contact’ for reporting ornamental plants in gardens with invasive potential. Invasive species are one of the five drivers of the global nature crisis, many of which were originally introduced through ornamental horticulture. Ornamentals confined to gardens and those which have already naturalised, but are not yet shown to be invasive, represent a ‘pool’ of species with invasive potential – ‘future invaders’. An online survey asking gardeners to report ornamentals they had noticed invading or taking over their garden resulted in 251 different taxa being reported (including cultivars). The future invaders were prioritised with a simple yet structured scheme, looking at the domestic and global naturalised and invasive status of each taxon, including in the Global Register of Introduced and Invasive Species (GRIIS) and the Global Naturalized Alien Flora (GloNAF) databases. The structured scheme identified a shortlist of nine ornamentals of concern which should be prioritised for further analysis, such as a formal risk assessment. Identifying and preventing future invaders before they escape gardens is critical, to prevent future threats to nature. There is also a gap in the identification of potentially invasive ornamentals, which are not currently invasive, yet are beyond the scope of formal horizon scanning because they are naturalised. Here we explore whether surveying gardeners can be a suitable approach to prioritising future invaders while also being an opportunity to increase awareness of invasive species. This positive feedback loop between gardeners and invasion scientists could help reduce the risk of future invaders

#UKRAS22: The 5th UK Robotics and Autonomous Systems Conference

© 2022 EPSRC UK-Robotics and Autonomous Systems (UK-RAS) Network. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/As chairs of the UKRAS 2022 conference, we are happy to welcome you in person after a break from in-person events. The theme of this year’s conference is “Robotics for Unconstrained Environments”, reflecting much of the robotics research that happens at Aberystwyth University. Unconstrained environments include any indoor and outdoor environment that has not been modified specifically for the robot to perform its task. The premise is that the environment must be representative of the task rather than being artificially simplified