Biology subjects

Mangin, P. H.

Publications and source records attributed to Mangin, P. H..

5 recordsLinked to original sources

bioRxiv2025

Tumoral CD24 tunes platelets binding and pro-metastatic functions

One of the earliest steps of breast cancer metastasis occurs when tumor cells (TCs) disseminate through the bloodstream. There, they interact with several blood components. Among them, platelet favor TC survival and metastatic spread. While the binding of platelet to TC is highly variable, its molecular controls and downstream consequences remain unidentified. Here, we first document that high CD24 expression correlates with increased platelet binding and poorer survival in breast cancer. We further demonstrate that CD24-mediated platelet binding regulates TC cluster formation and resistance to anoikis in vitro. Depleting CD24 expression significantly reduces TC metastatic potential by rewiring the metastatic tumor microenvironment (mTME), affecting immune compartments and secreted factors. Overall, our work identifies CD24 as a molecular cue controlling TC-platelet interaction, dictating their metastatic potential. As such, it represents a druggable target to counteract platelet-TC collaboration in metastasis.

cancer biology↗

bioRxiv2024

Staying on track: collagen fibers orientation strongly affects thrombi formation at high shear

ObjectiveSubendothelial matrix exhibits a distinctive organization, with collagen fibers beneath the endothelium oriented primarily parallel to the flow and comprising mainly types III and I collagen in arteries and arterioles. However, the significance of such organization in initiating rapid thrombus formation remains unclear. Approach and ResultsTo investigate the role of collagen fibers orientation in triggering thrombus formation we utilized the in vitro microfluidic model of thrombosis. Human whole blood was perfused through a system with collagen fibers oriented either parallel or perpendicular to the flow, and the primary stages of platelet adhesion and thrombi growth were analyzed using a high-speed fluorescence microscopy. At the shear rates of 200 and 1000 s-1 no significant difference in thrombogenicity was observed between the collagen fibers orientations. However, at a high shear rate of 2000 s-1, thrombi on the parallel fibers were higher and covered a much larger area than those on the perpendicular ones. High-speed microscopy revealed that platelets were able to achieve stable adhesion only after translocating for over several seconds under all studied conditions. Analysis of single platelets dynamics revealed that platelets interacted longer and translocated farther during their interaction with parallel fibers at high shear, suggesting that flow-aligned fibers facilitate stable adhesion by enabling platelets to translocate along them and stay in contact with collagen. Importantly, only a small fraction of collagen fibers belonging to type III collagen admixture - a common component of a standard type I collagen preparation - accumulated plasma vWF and supported platelet adhesion at high shear rate. ConclusionType III, but not type I collagen fibers oriented parallel to the flow facilitate stable platelet adhesion at high shear rates. Thus, axial orientation of subendothelial collagen fibers observed in vivo may have physiological relevance for triggering rapid thrombus formation at high shear rates. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/627297v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@14c1af5org.highwire.dtl.DTLVardef@17dffceorg.highwire.dtl.DTLVardef@12548d1org.highwire.dtl.DTLVardef@cfc431_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Depletion of all platelet integrins impacts hemostasis, thrombosis and tumor metastasis

Platelet integrins, in addition to other platelet receptors, are known to control hemostasis, thrombosis but also metastatic progression. Yet, their exclusive but combined deficiency has never been tested in these processes. Taking advantage of PF4Cre-{beta}1-/-/{beta}3-/- mouse strain, we show that platelets are exclusively depleted for all integrins. While they displayed impaired binding to fibrinogen and annexin-V, P-selectin exposure was normal. Platelet adhesion was abrogated on immobilized fibrinogen and fibrillar fibronectin under shear flow. PF4Cre-{beta}1-/- /{beta}3-/- mice presented an increased bleeding time and a profound defect in experimental models of arterial thrombosis. Platelet adhesion to tumor cells was also reduced, with a profound impact on tumor growth and metastatic burden in a model of triple negative breast cancer. Overall, these results confirm the central role of platelet integrins in hemostasis and thrombosis, and define their role in tumor growth and metastasis formation. 40-word summary: Depletion of all platelet integrins in PF4Cre-{beta}1-/-/{beta}3-/- mice leads to increased bleeding time and inhibits in vivo arterial thrombosis. Integrin-null platelets reduce tumor growth and metastatic burden in orthotopic and experimental metastasis models. Platelet integrins control hemostasis, thrombosis and metastasis.

cancer biology↗

bioRxiv2023

Initial platelet aggregation in the complex shear environment of a punctured vessel model

To analyze flow conditions and cellular behavior at the onset of a hemostatic response in the injury of a microneedle-induced vessel puncture, a combined in silico and in vitro platform is created. A cell-resolved blood flow model is utilized for in-depth flow profile and cell distribution analyses and a novel punctured vessel flow chamber is set up to complement the simulations with the evaluation of platelet aggregation around the wound neck of the puncture. The respective setups of the platform are explained and the results of both experiments and simulations with various puncture diameters and pressure drops are combined, providing detailed insight into the basic processes of platelet transport and aggregation in the wound area. A special emphasis of the simulation evaluation is put on the cell distributions and the magnitude of shear rate and elongational flow in the wound neck area, as well as downstream from the puncture. Additionally, possible implications of wound size and pressure difference on the hemostatic response are discussed. The simulations display asymmetric cell distributions between the proximal and distal side of the wound neck in regards to flow direction. The flow chamber with the puncture diameter closest to the simulated domains confirms this asymmetry by displaying increased platelet aggregation at the wound necks distal side. The presented punctured vessel in silico and in vitro experimental setups offer a platform to analyze the hemostatic environment of a vessel injured by a puncture and might assist in identifying differentiating factors between primary hemostasis and arterial thrombosis.

biophysics↗

bioRxiv2022

Platelets favor the outgrowth of established metastases

Despite abundant evidence demonstrating that platelets foster metastasis, a therapeutic approach based on anti-platelet agents is not an option due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals carrying growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

cancer biology↗