Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1287998 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy based on live microorganisms has shown promise in preclinical studies, but its clinical translation has been hampered by limited efficacy and innegligible toxicity. Here, we developed M-BLAST (Macrophage-Bacteria encapsulation Lytic Autoactivated Synergistic Therapeutics), a dual-gated macrophage-mediated bacterial tumor-targeted delivery and in situ activation system. M-BLAST incorporates density-regulated virulence-enhanced attenuated Salmonella strains as the therapeutic core, thermally-controlled GSDMD-N-expressing macrophages as the delivery vector, and copper selenide, a photothermal material, as a heat-shock “primer.” Following systemic administration, localized near-infrared irradiation at the tumor site triggers macrophage pyroptosis, ensuring rapid and complete bacterial release. This disrupts the immunosuppressive tumor microenvironment and elicits a widespread cascading antitumor response just like a “immune bomb”, while dual-gating design of bacterial density and heat-shock ensures safety by preventing off-target activation in non-tumor regions. M-BLAST promises to enhance the therapeutic utility of living engineered bacteria for cancer while ensuring safety.
2025-12-19 | GSE291419 | GEO
Project description:Due to low numbers and poor accessibility of host cells that are targeted for effector delivery, the actual biological functions of most effectors remain elusive. Here, we developed a novel Isolation Nuclei TArgeted by Bacterial Effectors (INTABE) system, which facilitates selectively recovering nuclei of the cells in Arabidopsis thaliana plants that have received type-III effectors of pathogenic Xanthomonas bacteria. Using these nuclei as studying materials, we analysed changes in host gene expression and their correlation with changes in DNA methylation induced by Xanthomonas effector Outer Protein D (XopD).
2022-10-22 | E-MTAB-10281 | biostudies-arrayexpress
Project description:ntroduction: Recent studies have discovered lung cancer subtypes to have their own profile of microbiome within the tumor microenvironment. Additionally, the tumor associated microbiome exhibited altered bacterial pathways, suggesting that certain bacterial families are more fit to facilitate tumor progression than others. We believe that there exists a crosstalk between lung adenocarcinoma cells (LUAD) and bacterial cells. Methods and Materials: RNA-seq was performed on LUAD cell lines to understand the paracrine signaling effects that bacterial biomolecules have. From our RNA-seq data, we chose to investigate glycolysis by measuring glucose uptake and lactate production, investigate invasive potential through invasion assays, and measure EMT markers. As lipopolysaccharides (LPS) are found abundantly on the cell wall of gram-negative bacteria and can activate toll like receptor 4 (TLR4), we inhibited TLR4 with C34 to determine the relationship between TLR4 and the phenotypic changes. Finally, to gain a better understanding of the bacterial biomolecules leading to the changes observed, we treated our media with either RNAse, charcoal, or dialyzed molecules > 3kDa. Results and Discussion: From our RNA-seq data, we observed a total of 948 genes upregulated in the presence of E. coli biomolecules. Of the 948 upregulated genes observed in LUAD cell lines incubated in E. coli biomolecules, we witnessed increased expression of Hexokinase II, JUN proto-oncogene, and Snail Family Transcriptional Repressor 1. We verified the elevation of glycolytic enzymes through western blot and saw elevation of 2-deoxyglucose uptake and lactate production in LUAD cell lines incubated in E. coli biomolecules using scintillation counter and lactate luminescence assay, respectively. In addition to E. coli elevating glycolysis in LUAD cell lines, we also saw increase in invasive potential by Boyden chamber. Inhibition of TLR4 did not lead to decreasing the impact of E. coli biomolecules on glycolysis or invasive potential of LUAD. Modulating our E. coli supplemented media with either RNAse, dextran-coated charcoal, or using a spin column to remove biomolecules < 3kDa resulted in changes in HKII and Claudin protein expression. Overall, these findings indicate a direct relationship between E. coli and LUAD, wherein several well-known hallmarks of cancer are upregulated. Future studies would do well in investigating these molecules further and fully understanding the impact of a microbial shift in the tumor microenvironment.
2025-02-19 | GSE286573 | GEO
Project description:Due to low numbers and poor accessibility of host cells that are targeted for effector delivery, the actual biological functions of most effectors remain elusive. Here, we developed a novel Isolation Nuclei TArgeted by Bacterial Effectors (INTABE) system, which facilitates selectively recovering nuclei of the cells in Arabidopsis thaliana plants that have received type-III effectors of pathogenic Xanthomonas bacteria. Using these nuclei as studying materials, we analysed changes in host gene expression and their correlation with changes in DNA methylation induced by Xanthomonas effector Outer Protein D (XopD).
2022-10-22 | E-MTAB-10280 | biostudies-arrayexpress
Project description:Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapted an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identified a naturally-evolved and serotype-specific interaction of AAV9 with human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density-lipoprotein-receptor-related-protein 6 (LRP6) interactions specific to engineered capsids that cross the blood-brain barrier in non-human primates upon intravenous administration. The unbiased cell microarray screening approach also allowed us to identify off-target tissue binding interactions of engineered brain-enriched AAVs that may inform vectors’ peripheral organ tropism and side effects. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.
2024-07-31 | PXD045380 | Pride
Project description:Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and meningiomas. The objective of this study was to develop an SSTR2-targeted therapy to treat both tumor types. We engineered and humanized an anti-SSTR2 monoclonal antibody (mAb) demonstrating strong cancer cell binding, internalization in cancer cells, and tumor specificity, as evidenced by flow cytometry, confocal microscopy, and live-animal imaging. Antibody-drug conjugates (ADCs) were generated by conjugating the SSTR2 mAb with potent payloads, including monomethyl auristatin F (MMAF) or mertansine (DM1). In vitro assessments revealed high cytotoxicity across diverse NET subtypes and meningioma cell lines. In vivo efficacy was confirmed in two mouse models, i.e. subcutaneous NET xenografts and intracranial meningioma xenografts, where treatment inhibited proliferation, induced apoptosis and cell death, exhibited minimal toxicity, and extended survival. The mechanism of action was further elucidated through bulk RNA sequencing post-treatment. These findings highlight the therapeutic potential of our humanized SSTR2 mAb for targeted payload delivery in NETs and meningiomas.
2025-08-12 | GSE304978 | GEO
Project description:Directed evolution in mammalian cells can facilitate the engineering of mammalian-compatible biomolecules and can enable synthetic evolvability for mammalian cells. We engineered an orthogonal alphaviral RNA replication system to evolve synthetic RNA-based devices, enabling RNA replicase-assisted continuous evolution (REPLACE) in live mammalian cells. Toinvestigatetheexpressionheterogeneityofself-replicatingRNAsinrepRNA-v4cells,weperformedsingle-cellRNA-seqanalysisusingthe10xGenomicssequencingmethod.Ouranalysisofthesingle-cellRNA-seqprofilingdatarevealedarelativelyuniformexpressionpatternofself-replicatingRNAswithinrepRNA-v4cells.
2024-07-07 | GSE235341 | GEO
Project description:Antibody-based therapeutics encompass diverse modalities for targeting tumor cells, among which antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. However, many tumor antigens exhibit poor internalization, limiting ADC effectiveness. To address this, we developed low-density lipoprotein receptor-targeting chimeras (LIPTACs), leveraging the constitutive endocytic and recycling activity of the low-density LDLR to enhance lysosomal delivery. LIPTACs enable robust degradation of diverse extracellular membrane proteins, including neo-epitopes on RAS-driven cancer cells. Moreover, by coupling LIPTACs with cytotoxic payloads to generate degrader-drug conjugates, we achieve superior intracellular delivery and enhanced cytotoxicity compared to conventional ADCs.
2025-11-10 | PXD064642 | Pride
Project description:Engineered macrophage-based therapies offer promising potential for cancer treatment but are limited by slow, uncontrolled drug release and the risk of macrophage reprogramming into tumor-promoting phenotypes. Here, we developed a thermally induced macrophage autolysis release system, the macrophage-microbe encapsulation bomb (MME-Bomb), which combines engineered macrophages loaded with indocyanine green (ICG)-encapsulated nanoparticles and antitumor attenuated Salmonella typhimurium strain. This system utilizes photothermally triggered pyroptosis to induce controlled macrophage rupture within the tumor microenvironment, releasing intracellular bacteria to stimulate prolonged antitumor immunity. By integrating light-responsive biomodulation, our approach enables site-specific activation of engineered cells, enhancing the rapid delivery of therapeutic agents and maximizing the synergy between macrophage-based and bacterial therapies. In preclinical cancer models, MME-Bomb significantly reduces the tumor burden and improves survival outcomes, both alone and in combination with checkpoint inhibitors. This innovative strategy offers a versatile and precise framework for advancing cancer immunotherapies.
2025-12-19 | GSE291580 | GEO
Project description:Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin like growth factor 2 (IGF2). After showing initial efficacy with wild type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially-selective targeted protein degradation.
2024-02-27 | MSV000094184 | MassIVE