Clinical Proteomics: A Promise Becoming Reality

Abstract

Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative DementiasMolecular & Cellular ProteomicsVol. 22Issue 10PreviewIn Brief We review technologies used for body fluid protein biomarker discovery and translation to clinical practice. We address their main characteristics, their use in research and clinics, strengths and limitations, and a future perspective. Full-Text PDF Open AccessThe First Pituitary Proteome Landscape From Matched Anterior and Posterior Lobes for a Better Understanding of the Pituitary GlandMolecular & Cellular ProteomicsVol. 22Issue 1PreviewIn Brief Our study of the first pituitary proteome draft offers the following novelty; for the first time, we present an extensive proteomic database containing proteins from both the anterior and posterior lobes of healthy pituitary, identifying various pituitary-enriched proteins and their lobe specificities, followed by target verification of pituitary hormones; for the first time, we are describing three uPE1 and have demonstrated that S100 proteins, which are known markers for pituitary adenomas, showed their presence significantly in the posterior lobe. Full-Text PDF Open AccessSARS-CoV-2 Variants Show Different Host Cell Proteome Profiles With Delayed Immune Response Activation in Omicron-Infected CellsMolecular & Cellular ProteomicsVol. 22Issue 5PreviewIn Brief SARS-CoV-2 has mutated over the past years to numerous variants of concern (VOCs). Employing quantitative whole-cell proteomics, we elucidate host cell immune responses upon infection with ancestral B.1, VOCs Delta, and Omicron BA.1 strains. Molecular assays further illustrate reduced viral protein levels and delayed host immune pathway response upon infection with Omicron BA.1 when compared to B.1 and Delta. Overall, this study offers insights into host proteome profiles and distinct immune kinetics of ancestral B.1, Delta, and Omicron BA.1 strains. Full-Text PDF Open AccessProteomic Characterization of Acute Myeloid Leukemia for Precision MedicineMolecular & Cellular ProteomicsVol. 22Issue 4PreviewIn Brief Proteomic and genomic studies have identified new drug targets for acute myeloid leukemia (AML), leading to new therapeutic options for certain patient subpopulations. In addition, many other drugs are in advanced stages of clinical development and proteomics keeps uncovering targets of interest. Given the large number of new therapies likely to be available for AML in the near future, identification of proteomic signatures of response for each drug will be key to select the best treatment for a given patient. Full-Text PDF Open AccessSensitive, High-Throughput HLA-I and HLA-II Immunopeptidomics Using Parallel Accumulation-Serial Fragmentation Mass SpectrometryMolecular & Cellular ProteomicsVol. 22Issue 6PreviewIn Brief In-depth mass spectrometry–based profiling of human leukocyte antigen (HLA) peptides currently requires large amounts of sample, and off-line fractionation is frequently used to improve coverage. However, primary tissues are often input limited and therefore not amenable to such workflows. Here, we developed and optimized a single-shot acquisition strategy on the timsTOF single-cell proteomics for sensitive and high-throughput immunopeptidome analysis. We demonstrate >2-fold increase in identfied HLA-I peptides and propose multiple collision energy slopes for samples with different HLA-I peptide-binding motifs. Full-Text PDF Open AccessProspective on Imaging Mass Spectrometry in Clinical DiagnosticsMolecular & Cellular ProteomicsVol. 22Issue 9PreviewIn Brief Imaging mass spectrometry is an emerging technology for clinical applications in that it provides spatial molecular data within a tissue biopsy for patient diagnoses and prognoses. This article considers various aspects of the use of this technology for new imaging-based assays that include analyte selection, quality control/assurance metrics, data reproducibility, data classification, and data scoring. Full-Text PDF Open AccessCross-Linking Mass Spectrometry Uncovers Interactions Between High-Density Lipoproteins and the SARS-CoV-2 Spike GlycoproteinMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief Here we utilized cross-linking mass spectrometry (XL-MS) to investigate circulating protein interaction networks in the context of SARS-CoV-2. The spike glycoprotein was determined to interact with multiple proteins on high-density lipoprotein including ApoD. The interaction between spike and ApoD was confirmed in cells through affinity purification-MS. XL-MS upon recombinant spike and ApoD, coupled with structural modeling, identified ApoD to interact within the spike receptor-binding domain. However, ApoD overexpression in cultured cell lines did not influence SARS-CoV-2 replication or infection. Full-Text PDF Open AccessUncovering Protein Networks in Cardiovascular ProteomicsMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief In the present article, we review and critically assess existing methods for reconstructing protein networks and discuss when each method is preferred for applications in cardiovascular research. We demonstrate the necessity to reconstruct networks separately for each cardiovascular tissue type and disease entity and provide illustrative examples of the importance of taking into consideration relevant post-translational modifications. Finally, we demonstrate and discuss how the findings of protein networks could be interpreted using single-cell RNA-sequencing data. Full-Text PDF Open AccessFunctional Impact of Protein–RNA Variation in Clinical Cancer AnalysesMolecular & Cellular ProteomicsVol. 22Issue 7PreviewIn Brief Proteogenomic studies of clinical cancer samples highlight broad protein–RNA discrepancies. Using Clinical Proteomic Tumor Analysis Consortium (CPTAC) protein and mRNA data on eight indications, we show the impact of low RNA–protein correlations on key biological processes, signaling pathways, and drug targets. We demonstrate that low RNA–protein correlations lead to distinct cancer classification, suggesting that protein-based subtyping may unravel distinct clinical features not seen upon RNA measurements. These analyses show the critical role of protein analyses for phenotypic tumor characterization. Full-Text PDF Open AccessMass Spectrometry–Based Proteomics of Epithelial Ovarian Cancers: A Clinical PerspectiveMolecular & Cellular ProteomicsVol. 22Issue 7PreviewIn Brief We systematically reviewed the MS-based proteomics studies of epithelial ovarian cancer, and over 2000 clinical trials since 1990. None of MS-based protein assays has been adopted in clinic, and none of the drug targets firstly discovered by proteomics has advanced to phase 3 or 4. Stringent standards for study design of proteomics are required, and more in-depth analyses of dysregulated proteins are essential. Full-Text PDF Open AccessClinical Proteomics for Solid Organ TissuesMolecular & Cellular ProteomicsVol. 22Issue 11PreviewIn Brief For many years, immunohistochemistry has been the primary tool in pathology for protein localization and quantification in solid tissues, but it is poorly standardized and suffers from practical limitations. The field is ripe for novel complementary technologies to help with diagnosis. This perspective focuses on the issues hampering immunohistochemistry and highlights how liquid chromatography-tandem mass spectrometry in particular is well-positioned to complement existing testing. We also discuss where guidance is needed to ensure rigor in clinical environments. Full-Text PDF Open AccessIntegrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer’s DiseaseMolecular & Cellular ProteomicsVol. 22Issue 5PreviewIn Brief Mechanisms by which individuals with Alzheimer’s disease (AD) pathology avoid dementia are not well known. We employed multiplex tandem mass tag mass spectrometry (TMT-MS)–based proteomics to identify proteins linked with cognitive resilience to AD. Computational strategies identified NRN1 as a synaptic protein associated with resilience. Using models of AD, we demonstrated that NRN1 can facilitate dendritic spine resilience against amyloid-β (Aβ) and block Aβ-induced neuronal hyperexcitability. We assessed how NRN1 alters the proteome by TMT-MS, which revealed overlapping synapse-related biology with humans. Full-Text PDF Open AccessFunctional and Clinical Proteomic Exploration of Pancreatic CancerMolecular & Cellular ProteomicsVol. 22Issue 7PreviewIn Brief Pancreatic cancer is extremely lethal with limited therapeutic options. Identifying effective early-detection biomarkers and novel therapeutic targets is urgently needed. In this review, we describe recent advances in functional and clinical proteomic analyses of pancreatic cancer. Regarding functional proteomics, we highlight post-translational modifications–mediated intracellular signaling, and ligands and plasma membrane receptors–mediated intercellular signaling. In terms of clinical proteomics, we highlight bulk tissue and plasma proteomics for identification of diagnostic and therapeutic targets and spatial proteomics for studying tumor heterogeneity. Full-Text PDF Open AccessMulti-Omics Profiling for HealthMolecular & Cellular ProteomicsVol. 22Issue 6PreviewIn Brief Current medical care focuses on treating people after they become patients rather than to preventing illness, leading to high costs in treating chronic and late-stage diseases. Additionally, a “one-size-fits all” approach to healthcare does not take into account individual differences in genetics, environment, or lifestyle factors, decreasing the number of people benefiting from interventions. Rapid advances in multi-omics enabled deep phenotyping, which profiles the interaction of multiple levels of biology over time, empowers precision health approaches and is poised to transform future healthcare. Full-Text PDF Open AccessTen Years of Extracellular Matrix Proteomics: Accomplishments, Challenges, and Future PerspectivesMolecular & Cellular ProteomicsVol. 22Issue 4PreviewIn Brief The extracellular matrix (ECM) is a complex assembly of hundreds of proteins forming the architectural organizer of multicellular organisms. Over the past decade, bottom-up proteomics has become the method of choice to profile the composition of the ECM. This article reviews the state of the art in ECM proteomics research and illustrates how ECM proteomics has emerged as a powerful discovery pipeline for cancer biomarkers. This review also introduces resources available to facilitate the study of the ECM using proteomics. Full-Text PDF Open AccessUltrasensitive Protein Detection Technologies for Extracellular Vesicle MeasurementsMolecular & Cellular ProteomicsVol. 22Issue 6PreviewIn Brief To harness the full potential of extracellular vesicles (EVs) for clinical applications, it is necessary to find appropriate protein biomarkers that enable selective isolation of rare subpopulations of EVs. Many conventional protein detection technologies have limited sensitivity to detect low abundance biomarkers in EVs, limiting their use in EV research. In this perspective, we highlight advances in current ultrasensitive detection technologies, their limitations, and areas of potential growth in the future. Full-Text PDF Open AccessThe Role of Clinical Glyco(proteo)mics in Precision MedicineMolecular & Cellular ProteomicsVol. 22Issue 6PreviewIn Brief The increasingly mature toolbox with glycomic- and glycoproteomic strategies is applied for the development of biopharmaceuticals and the discovery and clinical evaluation of glycobiomarkers in various disease fields. In this perspective on clinical glycoproteomics, a parallel is made with earlier proposed tiers for protein quantification using mass spectrometry. Multimarker readouts are foreseen with the potential for longitudinal sampling and monitoring of glycomic features for diagnosis and treatment monitoring. The importance of accurate quantification of a multimarker panel is discussed. Full-Text PDF Open AccessProteome Mapping of the Human Pancreatic Islet Microenvironment Reveals Endocrine–Exocrine Signaling Sphere of InfluenceMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief We applied our Microdroplet Processing in One pot for Trace Samples (microPOTS) TMT platform to study the pancreatic islet microenvironment in the human pancreas. We were able to quantify over 6000 proteins from seven different regions within the same patient. Here we describe enhancements to existing computational approaches to extract functional hypotheses from this first-of-its-kind dataset. In addition to recapitulating known functions of the islet, we can identify specific immune and RNA processing activities with spatial heterogeneity in expression. Full-Text PDF Open AccessPlasma Proteomic Kinetics in Response to Acute ExerciseMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief After measuring 4163 circulating proteins before, during, and 1-h after treadmill exercise in 75 middle-aged adults, we found that 765 proteins changed at peak exercise, and the majority of these proteins returned to baseline abundance 1-h after. Of 56 proteins with sustained change at peak exercise and after rest, there was enrichment for known secreted proteins and association with cardiometabolic traits in an independent cohort, suggesting that these proteins may be promising candidates for further investigation. Full-Text PDF Open AccessDissecting Detergent-Insoluble Proteome in Alzheimer's Disease by TMTc-Corrected Quantitative Mass SpectrometryMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief Using the TMT-LC/LC–MS/MS method and a TMTc-based strategy to correct for ratio compression, we analyzed detergent-insoluble proteome from 30 human AD and control brain samples. We identified 84 proteins enriched in the detergent-insoluble fraction, accumulated in AD, and mostly containing low-complexity regions. Our study highlights AD pathological hallmarks resistant to detergent extraction, providing a list of proteins and pathways exclusively present in the detergent-insoluble proteome. Full-Text PDF Open AccessMS-Based Proteomics of Body Fluids: The End of the BeginningMolecular & Cellular ProteomicsVol. 22Issue 7PreviewIn Brief Mass spectrometry is by its nature well suited for identification of body fluid biomarkers and their routine measurement but has been held back by technological and conceptual constraints. Here, we show that improvements in throughput, streamlining, robustness, and study design are progressively overcoming these constraints and have recently enabled promising success stories. Cutting-edge scan modes, multiplexing, and sample preparation promise to further enhance the technology, which we envision will finally bring MS-based proteomics to the clinic. Full-Text PDF Open AccessAn Inflection Point in Cancer Protein Biomarkers: What was and What's NextMolecular & Cellular ProteomicsVol. 22Issue 7PreviewIn Brief Biomarkers are the highest value proposition in cancer medicine today. Despite progress in molecular sciences and evolving regulatory frameworks for biomarkers, the field has been more about promise than improving human health. Achieving precision medicine necessitates moving away from reductionist thinking to studying complex diseases as complex adaptive systems and defining biomarkers as representations of biological system states. This approach will enable redefining cancer as a disease of dysregulated communication, which could ultimately prove to be game changing for the field of biomarkers and the patients who will benefit. Full-Text PDF Open AccessAn Atlas of the Knee Joint Proteins and Their Role in Osteoarthritis Defined by Literature MiningMolecular & Cellular ProteomicsVol. 22Issue 8PreviewIn Brief Information gathered by the molecular analysis of knee joint tissues is essential to improve the management of knee osteoarthritis, the most prevalent rheumatic pathology. Pursuing one of the goals of the Human Proteome Project, we applied a systematic strategy based on literature mining to define a protein atlas of this organ, including the prioritization of the proteins most cited in its most representative tissues. Pathway analysis on these proteins depicted the most relevant processes contributing to OA pathophysiology. Full-Text PDF Open AccessProteomics: Progress and Promise of High-Throughput Proteomics in Chronic Kidney DiseaseMolecular & Cellular ProteomicsVol. 22Issue 6PreviewIn Brief Population genetics methods leverage advances in large-scale proteomic profiling to improve the accuracy of diagnostic tools and the identification of therapeutic targets for kidney disease. Full-Text PDF Open Access “Clinical proteomics” can be understood to encompass a spectrum of activity from pre-clinical discovery to applied diagnostics: proteomics applied to clinically relevant materials; proteomics addressing a clinical or or mass spectrometry or in the or clinical clinical Proteomics approaches are increasingly used to the biological of identify new proteins and pathways for therapeutic disease or treatment and This of Molecular and Cellular Proteomics a of primary and to clinical proteomics. 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