Biology subjects

Osmani, N.

Publications and source records attributed to Osmani, N..

7 recordsLinked to original sources

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↗

bioRxiv2024

Endothelial calcium firing mediates extravasation of metastatic tumor cells.

Metastatic dissemination is driven by genetical, biochemical and biophysical cues that favor the distant colonization of organs and the formation of life-threatening secondary tumors. We have previously demonstrated that endothelial cells (ECs) actively remodel during extravasation by enwrapping arrested tumor cells (TCs) and extrude them from the vascular lumen while maintaining perfusion. In this work, we dissect the cellular and molecular mechanisms driving endothelial remodeling. Using high-resolution intravital imaging in zebrafish embryos, we demonstrate that the actomyosin network of ECs controls tissue remodeling and subsequent TC extravasation. Furthermore, we uncovered that this cytoskeletal remodeling is driven by altered endothelial- calcium (Ca2+) signaling caused by arrested TCs. Accordingly, we demonstrated that inhibition of voltage-dependent calcium L-type channels impairs extravasation. Lastly, we identified P2X4, TRP, and Piezo1 mechano-gated Ca2+ channels as key mediators of the process. These results further highlight the central role of endothelial remodeling during extravasation of TCs and open avenues for successful therapeutic targeting. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/587188v2_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@16fdc30org.highwire.dtl.DTLVardef@e0ff22org.highwire.dtl.DTLVardef@18e2311org.highwire.dtl.DTLVardef@a06320_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Deciphering circulating tumor cells binding in a microfluidic system thanks to a parameterized mathematical model

The spread of metastases is a crucial process in which some questions remain unanswered. In this work, we focus on tumor cells circulating in the bloodstream, the so-called Circulating Tumor Cells (CTCs). Our aim is to characterize their trajectories under the influence of hemodynamic and adhesion forces. We focus on already available in vitro measurements performed with a microfluidic device corresponding to the trajectories of CTCs - without or with different protein depletions - interacting with an endothelial layer. A key difficulty is the weak knowledge of the fluid velocity that has to be reconstructed. Our strategy combines a differential equation model - a Poiseuille model for the fluid velocity and an ODE system for the cell adhesion model - and a robust and well-designed calibration procedure. The parameterized model quantifies the strong influence of fluid velocity on adhesion and confirms the expected role of several proteins in the deceleration of CTCs. Finally, it enables the generation of synthetic cells, even for unobserved experimental conditions, opening the way to a digital twin for flowing cells with adhesion.

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↗

bioRxiv2018

Intravascular arrest of circulating tumor cells is a two-step process exploiting their adhesion repertoire.

Cancer metastasis is a process whereby a primary tumor spreads to distant organs. We have previously demonstrated that blood flow controls the intravascular arrest of circulating tumor cells (CTCs), through stable adhesion to endothelial cells. We now aim at defining the contribution of cell adhesive potential and at identifying adhesion receptors at play. Early arrest is mediated by the formation of weak adhesion depending on CD44 and integrin v{beta}3. Stabilization of this arrest uses integrin 5{beta}1-dependent adhesions with higher adhesion strength, which allows CTCs to stop in vascular regions with lower shear forces. Moreover, blood flow favors luminal deposition of fibronectin on endothelial cells, an integrin 5{beta}1 ligand. Finally, we show that only receptors involved in stable adhesion are required for subsequent extravasation and metastasis. In conclusion, we identified the molecular partners that are sequentially exploited by CTCs to arrest and extravasate in vascular regions with permissive flow regimes.

cancer biology↗

bioRxiv2017

Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells

Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. Altogether, these results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.

cancer biology↗

bioRxiv2017

An Arf6- And Caveolae-Dependent Pathway Links Hemidesmosome Remodeling And Mechanoresponse

Hemidesmosomes (HDs) are epithelial-specific cell-matrix adhesions, which stably anchor the intracellular keratin network to the extracellular matrix. Although their main role is to protect the epithelial sheet from external mechanical strain, how HDs respond to mechanical stress remains poorly understood. Here we identify a pathway essential for HD remodeling, and outline its role with respect to 6{beta}4 integrin recycling. We find that 6{beta}4 integrin chains localize to the plasma membrane/caveolae and Arf6+ endocytic compartments. Based on FRAP and endocytosis assays, integrin recycling between both sites requires the small GTPase Arf6 and its co-regulators GIT1/{beta}PIX, but neither Caveolin1 (Cav1) nor Cavin1. Strikingly, when keratinocytes are stretched or hypo-osmotically shocked, 6{beta}4 integrin accumulates at cell edges, whereas Cav1 disappears from it. This process, which is isotropic relative to the orientation of stretch, depends on Arf6, Cav1 and Cavin1. We propose that mechanically-induced HD growth involves the isotropic flattening of caveolae (known for their mechanical buffering role) associated with integrin diffusion and turnover.

cell biology↗