Gounis, M. | Search bioRxiv

bioRxiv2024

Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments

Altered cellular metabolism has been associated with acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumour resection to generate isogenic cells from primary tumours and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism leading to increased intracellular levels of specific ceramides. The combination of these two metabolic adaptations alters small extracellular vesicle (sEV) production to drive generation of an invasive microenvironment. Indeed, micrometastatic cells shut-down Rab27-dependent production of sEVs and, instead, switch-on neutral sphingomyelinase-2 (nSM2)-dependent sEV release. sEVs released in a nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing sEV release. SummaryBreast cancer cells isolated from lung micrometastases have altered metabolism which influences extracellular vesicle production to generate invasive microenvironments.

cancer biology↗

bioRxiv2022

Development of a clot-adhesive coating to improve the performance of thrombectomy devices

BackgroundThe first-pass complete recanalization by mechanical thrombectomy (MT) for the treatment of stroke remains limited due to the poor integration of the clot within current devices. Aspiration can help retrieval of the main clot but fails to prevent secondary embolism in the distal arterial territory. The dense meshes of extracellular DNA, recently described in stroke-related clots, might serve as an anchoring platform for MT devices. ObjectiveEvaluate the potential of DNA reacting surface to aid the retention of the main clot as well as of its small fragments within the thrombectomy device and improve the potential of MT procedures. MethodsDevice-suitable alloy experimental samples were coated with 15 different compounds and contacted with extracellular DNA or with human peripheral whole blood, to compare their binding to DNA versus flowing blood elements, in vitro. Clinical-grade MT devices were coated with two selected compounds and evaluated in functional bench tests aiming to studying clot retrieval and distal emboli release, concomitant with contact aspiration, using an M1 occlusion model. ResultsBinding properties of samples coated with all compounds were increased for DNA ({approx} 3-fold) and decreased ({approx} 5-fold) for blood elements, essentially platelet, as compared to the bare alloy samples, in vitro. Functional testing showed that surface modification with DNA-binding compounds improved clot retrieval and significantly reduced secondary embolism during experimental recanalization of occluded artery 3D model by thrombectomy procedures. ConclusionOur results suggest that device coating with DNA-binding compounds can considerably improve the outcome of MT procedures in stroke patients. What is already known on this topic - New mechanical thrombectomy device are being improved on the conformation and shape to increase the interaction clot on the physical point of view. However, none interact specifically with the structure or composition of the clot. What this study adds - The design of a chemical surface modification of the device opens the way for a specific targeting tool to increase the interaction with the clot on the molecular level. How this study might affect research, practice or policy - This new surface modification, which can be applied to all commercially available mechanical thrombectomy devices, leads to a decrease in secondary embolization which cannot and is not monitored during the procedure and responsible for new territory damage.

bioengineering↗