Biology subjects

Mittelheisser, V.

Publications and source records attributed to Mittelheisser, V..

7 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

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↗

bioRxiv2024

Nanomaterials trigger functional responses in primary human immune cells

Targeting the immune system with nanoparticles (NPs) to deliver immunomodulatory molecules emerged as a solution to address intra-tumoral immunosuppression and enhance therapeutic response. While the potential of nanoimmunotherapies in reactivating immune cells has been evaluated in several preclinical studies, the impact of drug-free nanomaterials on the immune system remains unknown. Here, we characterize the molecular and functional response of human NK cells and pan T cells to a selection of five NPs that are commonly used in biomedical applications. After a pre-screen to evaluate the toxicity of these nanomaterials on immune cells, we selected ultrasmall silica-based gadolinium (Si-Gd) NPs and poly(lactic-co-glycolic acid) (PLGA) NPs for further investigation. Bulk RNA-sequencing and flow cytometry analysis showcase that PLGA NPs trigger a transcriptional priming towards activation in NK and pan T cells. While PLGA NPs improved NK cells anti-tumoral functions in cytokines-deprived environment, Si-Gd NPs significantly impaired T cells activation as well as functional responses to a polyclonal antigenic stimulation. Altogether, we identified PLGAs NPs as suitable and promising candidates for further targeting approaches aiming to reactivate the immune system of cancer patients.

immunology↗

bioRxiv2024

Reinforced polymer-nanoparticle hydrogels for subcutaneous and sustained delivery of trastuzumab

In oncology, the advent of monoclonal antibody (mAbs) therapeutics represents a major breakthrough in various cancer diseases. However, these biotherapies often necessitate iterative hospital visits for intravenous infusion that can alter patients quality of life and contribute to the chronic saturation of hospitals. Interestingly, subcutaneous formulations of various mAbs offer a promising alternative facilitating faster administration compared with traditional intravenous methods, while still maintaining the same dosing schedule and providing time-saving advantages. Here, we developed an injectable mAb delivery platform using -cyclodextrin (CD)-reinforced polymer-nanoparticle hydrogels to perform a subcutaneous injection but also to delay the release of mAbs. By leveraging the versatility of our platform, we formulated hyaluronic acid- and alginate-based injectable drug depots by simply mixing components that are generally regarded as safe (GRAS). We used trastuzumab for the polymer-antibody complexation. The hydrogel depots delayed mAb release up to at least 3 days in both in vitro and in vivo mice models, outperforming clinically approved Herceptin subcutaneous formulation composed of trastuzumab with recombinant human hyaluronidase (rHuPH20).

bioengineering↗

bioRxiv2024

Cell viscosity influences hematogenous dissemination and metastatic extravasation of tumor cells

Metastases arise from a multi-step process during which tumor cells change their mechanics in response to microenvironmental cues. While such mechanical adaptability could influence metastatic success, how tumor cell mechanics directly impacts intravascular behavior of circulating tumor cells (CTCs) remains poorly understood. In the present study, we demonstrate how the deformability of CTCs affects hematogenous dissemination and identify the mechanical profiles that favor metastatic extravasation. Combining intravital microscopy with CTC-mimicking elastic beads and mechanically-tuned tumor cells, we demonstrate that the inherent properties of circulating objects dictate their ability to enter constraining vessels. We identify cellular viscosity as the key property that governs CTC circulation and arrest patterns. We further demonstrate that cellular viscosity is required for efficient extravasation and find that properties that favor extravasation and subsequent metastatic outgrowth can be opposite. Altogether, we identify CTC viscosity as a key biomechanical parameter that shapes several steps of metastasis.

cancer biology↗

bioRxiv2023

Targeting monocytic Occludin impairs monocyte transmigration and HIV neuroinvasion

Transmigration of circulating monocytes from the bloodstream toward the central nervous system (CNS) represents a hallmark of neuroinflammation and plays an important role during viral encephalitis and HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in monocyte transmigration through endothelia has been extensively studied, but how monocytes locally unzip tight junction-associated proteins (TJAPs) of the endothelium composing the neurovascular unit (NVU) to reach the CNS remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through cerebral microvessel endothelial cells. Silencing monocytic OCLN (mOCLN) impairs monocyte transmigration, while mOCLN overexpression increases transmigration. Using high-resolution live cell imaging, we observed that mOCLN clusters at the monocyte-endothelium interface during the transmigration process, forming a transient ring of mOCLN at the site of diapedesis. Furthermore, we designed OCLN-derived peptides targeting its extracellular loop (EL) 1 or 2 to prevent potential trans-homotypic interactions of mOCLN with endothelial OCLN. We found that transmigration of human monocytes was significantly inhibited upon treatment with the EL2 peptide in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and here, we showed that the treatment of transmigrating monocytes with the EL2 peptide prevents the dissemination of HIV to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent HIV neuroinvasion.

cell biology↗

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↗