Proteotranscriptomic decoding of the surface-endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche [U87_mRNA_Norm_Hyp]
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PROVIDER: PRJNA1029990 | ENA |
REPOSITORIES: ENA
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Project description:Proteotranscriptomic decoding of the surface-endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche
| PRJNA1029908 | ENA
Project description:Backgroung: Antibody and cell-based immunotherapies, e.g., antibody-drug-conjugates and CAR-T cells, targeted at cell-surface proteins, currently revolutionize clinical oncology. However, target selection warrants a better understanding of the surface-endocytome and how it is modulated by the tumor microenvironment. Here, we unravel the surface-endocytome landscape and its remodeling by hypoxia in primary cultures from glioblastoma (GBM) patients that currently lack targeted therapies. Methods. We employed a comprehensive approach for global and dynamic mapping of surfaceome and endocytosed (endocytome) proteins in primary GBM cultures at normoxia or hypoxia. Selected target candidates were validated by immunofluorescence analyses in patient tumor sections, spheroids, and 2D cultures, and were finally confronted by ADC cytotoxicity studies. Results: We reveal a heterogeneous surface-endocytome profile across GBM cultures from three patients representing different transcriptional subtypes. CD44 emerged as a commonly abundant surfaceome antigen across GBM cultures, and we established a direct correlation between CD44 endocytic activity and ADC cytotoxicity. We elucidate how hypoxia profoundly reshapes the global surface-endocytome, and identify several hypoxia-induced antigens (CXADR, CD47, BSG, CD81, FXYD6), unique to or shared among GBM cultures. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and targeted mass spectometry. Conclusions: These studies provide a comperehensive map of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for target discovery. As proof-of-concept, we validate several proteins, either abundantly expressed in normoxia or induced by hypoxia, for further exploration as potential targets of immunotherapeutic approaches in GBM.
2023-10-28 | GSE245762 | GEO
Project description:Background: Antibody and cell-based immunotherapies, e.g., antibody-drug-conjugates and CAR-T cells, targeted at cell-surface proteins, currently revolutionize clinical oncology. However, target selection warrants a better understanding of the surface-endocytome and how it is modulated by the tumor microenvironment. Here, we unravel the surface-endocytome landscape and its remodeling by hypoxia in primary cultures from glioblastoma (GBM) patients that currently lack targeted therapies. Methods. We employed a comprehensive approach for global and dynamic mapping of surfaceome and endocytosed (endocytome) proteins in primary GBM cultures at normoxia or hypoxia. Selected target candidates were validated by immunofluorescence analyses in patient tumor sections, spheroids, and 2D cultures, and were finally confronted by ADC cytotoxicity studies. Results: We reveal a heterogeneous surface-endocytome profile across GBM cultures from three patients representing different transcriptional subtypes. CD44 emerged as a commonly abundant surfaceome antigen across GBM cultures, and we established a direct correlation between CD44 endocytic activity and ADC cytotoxicity. We elucidate how hypoxia profoundly reshapes the global surface-endocytome, and identify several hypoxia-induced antigens (CXADR, CD47, BSG, CD81, FXYD6), unique to or shared among GBM cultures. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and targeted mass spectrometry. Conclusions: These studies provide a comprehensive map of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for target discovery. As a proof-of-concept, we validate several proteins, either abundantly expressed in normoxia or induced by hypoxia, for further exploration as potential targets of immunotherapeutic approaches in GBM.
2023-10-28 | GSE245800 | GEO
Project description:Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.
2024-05-23 | PXD048880 | Pride
Project description:Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.
| S-EPMC10898066 | biostudies-literature
Project description:Proteotranscriptomic Characterization of Human Retinoblastoma
| PRJNA1159360 | ENA
Project description:Background: Retinoblastoma is a rare pediatric eye cancer caused by mutations in the RB1 gene, which regulates retinal cell growth. Early detection and treatment are critical for pre-venting vision loss and improving survival outcomes. This study aimed to perform an inte-grated proteotranscriptomic characterization of human retinoblastoma to provide a deeper understanding of disease biology and to identify novel therapeutic targets. Methods: Paired tumor and adjacent retinal tissue samples were dissected from seven eyes affected by retinoblastoma. The global transcriptome and proteome were determined using RNA sequencing and liquid chromatography-mass spectrometry from the same samples. The spatially resolved cellular landscape was assessed using Imaging Mass Cytometry (IMC). Results: The correlation between RNA and protein level was moderate (Pearson’s R = 0.339, p < 10-16) with variations across different pathways. While biological processes like visual perception were similarly regulated on the RNA and protein level, others, such as cell cycle processes and glycolysis were predominantly active at the protein level. IMC identified more than 67,000 single cells in distinct clusters, including antigen presenting cells, T cells, stroma cells, vascular cells and two clusters of proliferating and CD44/c-Myc positive tumor cells. In retinoblastoma, we observed increased apoptotic signals in T cells and higher ex-pression of CD68 in antigen presenting cells compared to control tissue. Conclusions: Retinoblastoma's key biological processes are predominantly regulated at either the RNA or protein level, underscoring the value of an integrated proteotranscriptomic approach. Elevated caspase 3 activity in tumor-associated T cells may indicate potential im-mune escape mechanisms and CD44+ and high-c-Myc-expressing tumor cells may repre-sent cancer stem cells with possible involvement in metastasis, warranting further validation. Our multilayered approach could pave the way for enhanced molecular assessments and novel targeted therapies for human retinoblastoma.
2025-05-29 | GSE276895 | GEO
Project description:Two Plasmodium cell surface antigens were transformed into Drosophila, un-induced flies were compared to induced flies.
2008-12-31 | E-MEXP-1859 | biostudies-arrayexpress
Project description:The soaring global monkeypox cases lead to a surge in demand for monkeypox vaccine, which far exceeds the supply. mRNA vaccine has achieved great success in prevention of coronavirus disease and holds promise against diverse pathogens. In this study, we generate a polyvalent lipid nanoparticle (LNP) mRNA vaccine candidate for monkeypox virus (MPXV) and evaluate its immunogenicity in animal models. This polyvalent MPXV mRNA vaccine candidate, MPXVac-097, encodes five 2022 MPXV targets that are important surface antigens. Three-dose (prime-boost-booster) MPXVac-097 vaccination elicits strong antibody response to A35R and E8L antigens, moderate response to M1R, but not B6R or A29, highlighting the differences in immunogenicity. Bulk T cell receptor (TCR) sequencing reveals preferential usage of VJ combinations and clonal expansion of peripheral T cells after MPXVac-097 vaccination. These data demonstrate initial feasibility of developing MPXV mRNA vaccine and pave the way for its future optimization.
2023-02-13 | GSE225183 | GEO
Project description:Decoding murine cytomegalovirus
| PRJNA874807 | ENA