Biology subjects

Manshian, B. B.

Publications and source records attributed to Manshian, B. B..

4 recordsLinked to original sources

bioRxiv2024

Longitudinally cultured precision cut lung slices as a predictive ex vivo model for lung cancer

Exploring alternatives to in vivo models, this study validates Precision Cut Lung Slices (PCLS) as a viable ex vivo platform for lung cancer research. We established the prolonged viability and structural preservation of PCLS, essential for accurate drug response studies. Using Paclitaxel as a benchmark drug and a therapeutically promising silver nanoparticles in combination with immunotherapy, we conducted a pioneering comparative analysis of its therapeutic effects on PCLS against traditional in vivo models. Results revealed that PCLS closely mimics in vivo responses, demonstrating comparable drug efficacy in tumor growth inhibition. This direct comparison not only confirms the utility of PCLS in simulating real-world outcomes but also emphasizes its potential in reducing animal testing. By providing a reliable, ethical, and efficient alternative for lung cancer studies, PCLS could significantly enhance preclinical research and drug development, marking a critical step towards more humane and representative scientific investigations.

cancer biology↗

bioRxiv2024

Silver nanoparticle induced immunogenic cell death can improve immunotherapy

Cancer immunotherapy is often hindered by an immunosuppressive tumor microenvironment (TME). Various strategies are being evaluated to shift the TME from an immunologically cold to hot tumor and hereby improve current immune checkpoint blockades (ICB). One particular hot topic is the use of combination therapies. Here, we set out to screen a variety of metallic nanoparticles and explored their in-vitro toxicity against a series of tumor and non-tumor cell lines. For silver nanoparticles, we also explored the effects of core size and surface chemistry on cytotoxicity. Ag-citrate-5nm nanoparticles were found to induce high cytotoxicity in Renca cells through excessive generation of reactive oxygen species (ROS) and significantly increased cytokine production. The induced toxicity resulted in a shift of the immunogenic cell death (ICD) marker calreticulin to the cell surface in-vitro and in-vivo. Subcutaneous Renca tumors were treated with anti-PD1 or in combination with Ag-citrate-5nm. The combination group resulted in significant reduction in tumor size, increased necrosis, and immune cell infiltration at the tumor site. Inhibition of cytotoxic CD8+ T cells confirmed the involvement of these cells in the observed therapeutic effects. Our results suggest that Ag-citrate-5nm is able to promote immune cell influx and increase tumor responsiveness to ICB therapies.

cancer biology↗

bioRxiv2023

Vessel normalization and maturation promotes nanoparticle delivery to solid tumors while minimizing metastases.

Nanoparticle delivery to solid tumors is known to be an inefficient process and various studies have tried to increase efficacy, but mechanistic and comparative studies remain scarce. Here, we use pharmacological agents to study the effect of vessel normalization or vessel disintegration on nanoparticle delivery to solid tumors. Using a multiparametric approach, we find that vessel disintegration fails to improve nanoparticle delivery and instead seems to have a limiting effect. Vessel normalization, however, improves delivery efficacy for nanoparticles ranging from 20 to 60 nm diameter. The normalization of the tumor blood vessels results in reduced hypoxia, reduced necrosis and an increase in Plvap+ CD276+ endothelial cells, which have been linked with nanoparticle delivery. Interestingly, where vessel disintegration stimulated cancer cell intravasation and associated metastases, vessel normalization impeded these processes. Together, these data reveal that, vessel normalization may be a safer and more suited approach for improving nanoparticle delivery to solid tumors, but its efficacy is limited by nanoparticle diameter and tumor parameters. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/538559v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e5e08org.highwire.dtl.DTLVardef@14f82dcorg.highwire.dtl.DTLVardef@118708eorg.highwire.dtl.DTLVardef@18593d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

Multinucleation resets human macrophages for specialized functions at the expense of mononuclear phagocyte identity

Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. While osteoclast multinucleation is a prerequisite for vertebrate bone homeostasis, the effector function resulting from LGC and FBGC multinucleation is less well-defined. More generally, how multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrated comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced down-regulation of mononuclear phagocyte identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, only B7-H3 (CD276)-expressing human LGCs can form granuloma-like clusters in vitro, suggesting that LGC multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.

cell biology↗