Proteomics reveals the distinctive molecular features of early Alzheimer's disease

    Proteogenomic study of endometrial carcinoma

    A spatiotemporal proteomic map of human adipose tissue

    Prognostic study of ovarian cancer patients based on small extracellular vesicle proteomics

    Alzheimer's disease -associated glycoproteomic study

    Proteome-level study of the distribution and dynamic features of ubiquitination in mammalian cells

    Multi-omics analysis reveals candidate therapeutic targets in oesophageal adenocarcinoma

    Gut microbiome and metabolome analysis in the Framingham Heart Study

    Systematic characterisation of the microbiome of metastatic cancer

Proteomics reveals the distinctive molecular features of early Alzheimer's disease

Dysfunction of fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological disturbance in Alzheimer's disease (AD). Defining the early proteomic changes in PV-INs can provide key biological and translationally relevant insights. A research team at Emory University School of Medicine in the United States used cell-specific in vivo biotinylation of proteins (CIBOP) combined with mass spectrometry to obtain the native-state PV-IN proteome. The PV-IN proteomic signature included high metabolic and translational activity and overexpression of proteins related to AD risk and cognitive resilience. In bulk proteomes, PV-IN proteins were associated with human cognitive decline, human progressive neuropathology and Aβ pathology in the 5xFAD mouse model. At early stages of AD pathology, CIBOP of PV-INs revealed increased mitochondrial and metabolic features, disruption of synapses and the cytoskeleton and reduced mTOR signalling — features not evident in the whole-brain proteome. In addition, the researchers demonstrated a presynaptic deficit in PV-to-excitatory neurotransmission, validating the proteomic findings. The study presents the native-state proteome of PV-INs and reveals their distinctive role in cognitive resilience and AD pathogenesis.

The incidence of endometrial carcinoma (EC) continues to rise, particularly among younger women, and remains a public health problem. Fertility preservation is a key consideration in the treatment of early-onset endometrioid endometrial carcinoma (EEEC), especially for patients under 40 who wish to retain both the desire and the capacity to have children. To elucidate the molecular features of EEEC, the teams of Sun Chaoyang at Huazhong University of Science and Technology and Chen Xiaojun at Fudan University conducted a large-scale proteogenomic study of 215 EC patients, including 81 EEEC cases. The study revealed an association between environment-exposure-related mutational signatures and EEEC, characterised by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, the SIGLEC10Q144K mutation in EEEC leads to abnormal expression of the SIGLEC-10 protein and promotes progesterone resistance through interaction with oestrogen receptor α. The study also identified potential protein biomarkers of progesterone response in fertility-preserving treatment of EEEC. In summary, the study establishes a proteogenomic resource for EEEC, reveals the interplay between the environmental exposome and genomic susceptibility, and contributes to the development of primary prevention and early detection strategies for EEEC.

White adipocytes serve as the body's main energy reservoir by storing large amounts of triglycerides, and their dysfunction is linked to metabolic disorders. Yet the mechanisms of cell specialisation during adipogenesis remain unclear. Natalie Krahmer's team at the Helmholtz Diabetes and Obesity Research Institute in Munich, Germany, constructed a spatiotemporal proteomic map of human adipogenesis, clarifying the spatial reorganisation of cellular remodelling and metabolic pathways that optimises lipid accumulation in the cell and highlighting the coordinated regulation of protein localisation and abundance during adipocyte formation. The study identified compartment-specific regulation at the protein level and localisation changes of metabolic enzymes that reprogramme branched-chain amino acid and one-carbon metabolism to supply building blocks and reducing equivalents. In addition, the study found C19orf12 to be a differentiation-induced adipocyte lipid droplet protein that interacts with the outer membrane complex translocase of lipid-droplet-associated mitochondria and regulates lipid storage in adipocytes by determining the mitochondrial capacity to metabolise fatty acids.

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Prognostic study of ovarian cancer patients based on small extracellular vesicle proteomics

Tumour-derived small extracellular vesicles (sEVs) can remodel the tumour microenvironment and promote tumour progression. Ovarian cancer (OvCa) is a lethal malignancy that spreads preferentially through the peritoneal cavity, so the secretion of these vesicles into peritoneal fluid may be a determinant of the dissemination and behaviour of the disease. Researchers at the Hospital Universitario Sanchinarro in Madrid designed a prospective, observational study to assess the impact of peritoneal-fluid-derived sEVs (PFD-sEVs) on clinical outcomes in OvCa. The study enrolled two patient cohorts: OvCa patients undergoing diagnostic or debulking surgery, and non-oncological patients undergoing abdominal surgery for benign gynaecological disease as controls. PFD-sEVs systematically extracted from surgical samples showed significant quantitative and qualitative differences associated with cancer diagnosis, disease stage and sensitivity to platinum-based chemotherapy. Proteomic analysis of PFD-sEVs identified molecular pathways and proteins of interest, with biological validation of S100A4 and STX5. In addition, unsupervised analysis of the PFD-sEV proteomic profiles of high-grade serous ovarian carcinoma (HGSOC) revealed two clusters with different overall survival outcomes. The comprehensive characterisation of PFD-sEV content offers prognostic value with potential significance for the clinical management of HGSOC.

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Alzheimer's disease-associated glycoproteomic study

Protein glycosylation is essential to brain health, but current knowledge of glycosylated protein forms in the human brain and their changes in Alzheimer's disease (AD) is limited. A research team at Emory University School of Medicine in the United States used intact-glycopeptide-based quantitative glycoproteomics combined with systems biology to profile glycoforms across the whole proteome in the brains of AD patients and controls. More than 10,000 human brain N-glycoforms were identified from nearly 1,200 glycoproteins, revealing disease signatures of altered glycoform and glycan modification, including reduced sialylation and reduced N-glycan branching and elongation and increased mannosylation and N-glycan truncation in AD patients. Network analysis revealed the higher-order organisation of the brain glycoproteome, forming co-regulated glycoform and glycan networks, and identified glycoform and glycan modules associated with AD clinical phenotype, β-amyloid accumulation and tau pathology. These findings contribute a valuable perspective on the pathogenesis of AD and provide a rich resource of glycoform and glycan changes, offering ideas for the development of glycosylation-based AD therapies and biomarkers.

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Proteome-level study of the distribution and dynamic features of ubiquitination in mammalian cells

In eukaryotic cells, ubiquitination regulates most proteins and biological processes. Yet the site specificity and turnover rate of ubiquitination have not been quantified. Chunaram Choudhary's research team at the University of Copenhagen presented a comprehensive atlas of ubiquitination sites and half-lives, using mass-spectrometry-based proteomics to analyse the specific distribution and dynamic features of ubiquitination sites in mammalian cells. The results showed that ubiquitination levels differ by four orders of magnitude across sites, with an average level at least three orders of magnitude lower than phosphorylation. Proteasome inhibitors were found to be closely associated with site occupancy, turnover rate and regulation — features that distinguish sites involved in proteasomal degradation from those involved in cell signalling. Sites in structured protein regions showed longer half-lives and upregulation by proteasome inhibitors than sites in non-structured regions. More importantly, the authors discovered a special mechanism that rapidly deubiquitinates the ubiquitination-specific enzymes E1 and E2, protecting them from surrounding ubiquitination. This work is the first systematic quantitative study of ubiquitination and provides theoretical support for ubiquitination-dependent physiological processes.

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Multi-omics analysis reveals candidate therapeutic targets in oesophageal adenocarcinoma

Efforts to address the poor prognosis of oesophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers for identifying early disease and therapeutic targets. Javier Alfaro's team at the International Centre for Cancer Vaccine Science, University of Gdansk, performed quantitative proteomic analysis on matched adjacent normal oesophageal and gastric tissues from 23 EAC patients. Matched RNA-seq and proteomic data from 7 patients' tissues were used to explore the correlation between transcript and protein abundance, and these data were further integrated with an EAC RNA-seq cohort (n = 264 patients), EAC whole-genome sequencing (n = 454 patients) and externally published data sets. In the end, protein expression of 5,879 genes was quantified in EAC and patient-matched normal tissues, and several candidate biomarkers with adenocarcinoma-selective expression were identified, including the transmembrane protein GPA33; EAC-enriched expression of GPA33 was further validated in external cohorts, confirming it as an attractive diagnostic and therapeutic target. In addition, integrated analysis of protein and RNA expression in EAC and normal tissues revealed genes with low protein–RNA abundance correlation, indicating post-transcriptional regulation of protein expression. These aberrant genes included SLC25A30, TAOK2 and AGMAT, which rarely showed somatic mutations, suggesting post-transcriptional driver genes for this adenocarcinoma-specific phenotype. The study shows that AGMAT is overexpressed at the protein level in EAC compared with adjacent normal tissue, and proposes an EAC-selective post-transcriptional mechanism regulating protein abundance.

A growing body of research links cardiovascular disease (CVD) to changes in the composition of the gut microbiota, but understanding of the underlying mechanisms has been held back by the lack of multi-omics data matched to diagnostic biomarkers. To comprehensively characterise the contribution of the gut microbiome to CVD, Ramnik J. Xavier's team at the Broad Institute in the United States performed faecal metagenomics and metabolomics on 1,429 Framingham Heart Study participants. Blood lipids and cardiovascular health measures associated with microbiome and metabolome composition were identified. Integrated analysis revealed microbial pathways associated with CVD, including flavonoid, γ-butyrobetaine and cholesterol metabolism. Species of the genus Oscillibacter were associated with lower faecal and plasma cholesterol levels. Through functional prediction and in vitro characterisation of multiple representative human gut Oscillibacter isolates, the team found conserved cholesterol-metabolising capabilities, including glycosylation and dehydrogenation. These findings indicate that cholesterol metabolism is a widespread property of phylogenetically diverse Oscillibacter species, with potential benefits for lipid homeostasis and cardiovascular health.

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Systematic characterisation of the microbiome of metastatic cancer

Microbial communities inhabit multiple niches of the human body and are important modulators of the host immune system and of the response to anti-cancer therapy. Recent studies show that complex microbial communities exist in primary tumours. To investigate the presence and relevance of the microbiome in metastases, Emile Voest's team at the Netherlands Cancer Institute integrated mapping- and assembly-based metagenomics, genomics, transcriptomics and clinical data from 4,160 metastatic tumour biopsies, identifying organ-specific tropism of microbes, enrichment of anaerobic bacteria in hypoxic tumours, an association between microbial diversity and tumour-infiltrating neutrophils, and an association between Fusobacterium and resistance to immune checkpoint blockade (ICB) in lung cancer. In addition, longitudinal tumour sampling revealed the temporal evolution of microbial communities and identified bacteria depleted under ICB. This systematic analysis of the metastatic tumour microbiome by the research team will help advance therapeutic strategies.