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Cancers Mar 2024Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however,... (Review)
Review
BACKGROUND
Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes.
METHODS
A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis.
RESULTS
As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets.
CONCLUSIONS
An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer.
PubMed: 38539567
DOI: 10.3390/cancers16061236 -
Cells Mar 2024Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung...
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose-response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFβ1, IL6, TNFα, IL1β, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFβ/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model.
Topics: Rats; Humans; Animals; Procollagen; Idiopathic Pulmonary Fibrosis; Fibrosis; Collagen; Bleomycin; Disease Progression
PubMed: 38534359
DOI: 10.3390/cells13060515 -
Biological Imaging 2023Spatially resolved transcriptomics (SRT) is a growing field that links gene expression to anatomical context. SRT approaches that use next-generation sequencing (NGS)...
Spatially resolved transcriptomics (SRT) is a growing field that links gene expression to anatomical context. SRT approaches that use next-generation sequencing (NGS) combine RNA sequencing with histological or fluorescent imaging to generate spatial maps of gene expression in intact tissue sections. These technologies directly couple gene expression measurements with high-resolution histological or immunofluorescent images that contain rich morphological information about the tissue under study. While broad access to NGS-based spatial transcriptomic technology is now commercially available through the Visium platform from the vendor 10× Genomics, computational tools for extracting image-derived metrics for integration with gene expression data remain limited. We developed as a MATLAB pipeline to process, analyze and interactively visualize the high-resolution images generated in the Visium platform. outputs can be easily integrated with accompanying transcriptomic data to facilitate downstream analyses in common programing languages including R and Python. provides user-friendly tools for integrating image-derived metrics from histological and immunofluorescent images with spatially resolved gene expression data. Integration of this data enhances the ability to understand the transcriptional landscape within tissue architecture. is freely available at http://research.libd.org/VistoSeg/.
PubMed: 38510173
DOI: 10.1017/S2633903X23000235 -
Frontiers in Cellular and Infection... 2024Tularemia is a vector-borne disease caused by the Gram-negative bacterium . Known hosts and vectors in Europe are hare and ticks. is transmitted from ticks and animals,...
Tularemia is a vector-borne disease caused by the Gram-negative bacterium . Known hosts and vectors in Europe are hare and ticks. is transmitted from ticks and animals, but also from the hydrotelluric environment and the consumption of contaminated water or food. A changing climate expands the range in which ticks can live and consequently might contribute to increasing case numbers of tularemia. Two subspecies of are human pathogenic. is endemic in North America, while is the only subspecies causing tularemia in Europe. is classified as a category A bioterrorism agent due to its low infectious dose, multiple modes of transmission, high infectivity and potential for airborne transmission and has become a global public health concern. In line with the European survey and previous phylogenetic studies, Switzerland shows the co-distribution of B.6 and B.12 strains with different geographical distribution and prevalence within the country. To establish itself in different host environments of ticks and mammals, presumably undergoes substantial changes on the transcriptomics and proteomic level. Here we investigate the transcriptomic and proteomic differences of five strains of upon infection of rabbit macrophages and tick cells.
Topics: Animals; Humans; Rabbits; Francisella tularensis; Tularemia; Ticks; Phylogeny; Proteogenomics; Proteomics; Genotype; Mammals; Francisella
PubMed: 38500499
DOI: 10.3389/fcimb.2024.1355113 -
Nature Communications Mar 2024
PubMed: 38491045
DOI: 10.1038/s41467-024-46724-8 -
Science Bulletin May 2024Liver-tissue engineering has proven valuable in treating liver diseases, but the construction of liver tissues with high fidelity remains challenging. Here, we present a...
Liver-tissue engineering has proven valuable in treating liver diseases, but the construction of liver tissues with high fidelity remains challenging. Here, we present a novel three-dimensional (3D)-imprinted cell-sheet strategy for the synchronous construction of biomimetic hepatic microtissues with high accuracy in terms of cell type, density, and distribution. To achieve this, the specific composition of hepatic cells in a normal human liver was determined using a spatial proteogenomics dataset. The data and biomimetic hepatic micro-tissues with hexagonal hollow cross-sections indicate that cell information was successfully generated using a homemade 3D-imprinted device for layer-by-layer imprinting and assembling the hepatic cell sheets. By infiltrating vascular endothelial cells into the hollow section of the assembly, biomimetic hepatic microtissues with vascularized channels for nutrient diffusion and drug perfusion can be obtained. We demonstrate that the resultant vascularized biomimetic hepatic micro-tissues can not only be integrated into a microfluidic drug-screening liver-on-a-chip but also assembled into an enlarged physiological structure to promote liver regeneration. We believe that our 3D-imprinted cell sheets strategy will open new avenues for biomimetic microtissue construction.
Topics: Humans; Liver; Tissue Engineering; Biomimetics; Hepatocytes; Liver Regeneration; Lab-On-A-Chip Devices; Biomimetic Materials
PubMed: 38490890
DOI: 10.1016/j.scib.2024.02.030 -
NPJ Precision Oncology Mar 2024We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue...
We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.
PubMed: 38480868
DOI: 10.1038/s41698-024-00519-8 -
Nature Metabolism Apr 2024Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for...
Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.
Topics: Humans; Caloric Restriction; Proteome; Female; Male; Fasting; Adult; Weight Loss; Proteomics; Adaptation, Physiological
PubMed: 38429390
DOI: 10.1038/s42255-024-01008-9 -
Haematologica Jul 2024
Topics: Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Oncogene Proteins, Fusion; Proteogenomics; Translocation, Genetic; Basic Helix-Loop-Helix Transcription Factors; Pre-B-Cell Leukemia Transcription Factor 1
PubMed: 38426288
DOI: 10.3324/haematol.2023.283928 -
Cell Reports Methods Feb 2024Tumor deconvolution enables the identification of diverse cell types that comprise solid tumors. To date, however, both the algorithms developed to deconvolve tumor...
Tumor deconvolution enables the identification of diverse cell types that comprise solid tumors. To date, however, both the algorithms developed to deconvolve tumor samples, and the gold-standard datasets used to assess the algorithms are geared toward the analysis of gene expression (e.g., RNA sequencing) rather than protein levels. Despite the popularity of gene expression datasets, protein levels often provide a more accurate view of rare cell types. To facilitate the use, development, and reproducibility of multiomic deconvolution algorithms, we introduce Decomprolute, a Common Workflow Language framework that leverages containerization to compare tumor deconvolution algorithms across multiomic datasets. Decomprolute incorporates the large-scale multiomic datasets produced by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), which include matched mRNA expression and proteomic data from thousands of tumors across multiple cancer types to build a fully open-source, containerized proteogenomic tumor deconvolution benchmarking platform. http://pnnl-compbio.github.io/decomprolute.
Topics: Humans; Proteomics; Multiomics; Benchmarking; Reproducibility of Results; Neoplasms
PubMed: 38412834
DOI: 10.1016/j.crmeth.2024.100708