Ribosome Newsletter: Navigating the Convergence of Proteomics, AI, Synthetic Biology, and Translational Medicine
Welcome to this week’s edition of Ribosome, where we spotlight the latest advances in proteomics. This issue features a machine learning model enhancing pediatric thyroid cancer prognosis, a novel inhibitor targeting DNA repair enzymes in MSI-high cancers, and findings on how the NEDD8 gene influences immune responses in breast cancer therapy. We also delve into HBO1's role in cancer progression through histone modification, the impact of JAK2-driven phosphorylation in leukemia, and new chemoproteomics techniques that streamline ligand discovery. Plus, explore how food cues affect liver metabolism via mitochondrial dynamics, showcasing the intricate connections between diet and metabolic regulation. Join us as we explore these discoveries that hold the potential to transform patient care and therapeutic strategies.
Therapeutic Applications
A study developed a machine learning-based prognostic model to predict recurrence risks in pediatric patients with papillary thyroid carcinoma (PPTC), using clinical factors and proteomic analysis of 234 thyroid nodules. The analysis identified 243 significantly dysregulated proteins in pediatric malignant versus benign nodules and 121 versus adult malignant nodules, revealing enhanced immune system activation in pediatric malignancies. The model, based on nineteen key proteins, achieved 88% accuracy in classifying patients into high or low recurrence risk groups, offering a valuable tool for personalized treatment planning and clinical decision-making. This approach underscores the potential of proteomic profiling in improving prognosis evaluations and treatment strategies for pediatric thyroid cancer.
Researchers have identified a covalent allosteric inhibitor, VVD-133214, targeting WRN helicase, a critical enzyme in resolving harmful DNA structures in cells with deficient mismatch repair, such as those found in cancers with microsatellite instability (MSI). This clinical-stage compound uniquely binds to a specific cysteine within the helicase domain, disrupting the enzyme's flexibility and function, leading to significant DNA damage and cell death in MSI-high cells, but not affecting microsatellite-stable cells. The inhibitor demonstrated significant tumor regression in colorectal cancer models and was well tolerated in mice, marking it as a potent candidate for treating MSI-high cancers. This approach provides a novel pathway for targeting DNA repair mechanisms in cancer therapy without competing with ATP, the natural substrate of helicases.
In a study focused on triple-negative breast cancer (TNBC), researchers used genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System to identify vulnerabilities to immune checkpoint blockade therapy, particularly nivolumab. They discovered that loss of the NEDD8 gene in cancer cells significantly increased their susceptibility to immune attack following PD-1 blockade. This genetic deletion of NEDD8 initially delayed cell division without affecting overall cell proliferation after recovery. Furthermore, experiments demonstrated that NEDD8-deficient TNBC cells exhibited increased immunogenicity, leading to tumor regression and enhanced CD8+ T cell-mediated destruction in immunocompetent mice models treated with PD-1 blockade. This study highlights NEDD8 as a potential synergistic target for enhancing the efficacy of immune checkpoint inhibitors in treating TNBC.
Recent research revealed that the enzyme HBO1 serves as a lysine lactyltransferase that regulates gene transcription via histone H3K9 lactylation. HBO1 was shown to add lactyl groups both in vitro and within cells, significantly influencing gene expression patterns linked to key signaling pathways and cancer progression. Notably, CUT&Tag assays indicated that HBO1 is essential for the presence of histone H3K9 lactylation at transcription start sites, a modification that may enhance tumor malignancy. This study underscores the critical role of HBO1 in mediating a histone lactylation-dependent transcription regulation, pointing to its potential in cancer therapeutics.
领英推荐
In a recent study, researchers found that tyrosine phosphorylation of CARM1, driven by the activation of JAK2 kinase due to the V617F mutation, significantly boosts its enzymatic activity and modifies its target specificity. This phosphorylation event enables CARM1 to methylate the RUNX1 transcription factor at specific sites, enhancing gene expression linked to cell cycle progression and reducing apoptosis in myeloid leukemia cells. Interestingly, cells expressing a non-phosphorylatable variant of CARM1 showed impaired proliferation and increased cell death, highlighting the potential therapeutic value of targeting both JAK2 and CARM1 in treating hematologic malignancies where this pathway is activated.
Proteomics Innovations
A recent study utilized chemoproteomics to analyze protein-ligand interactions across the human proteome. Researchers screened around 400 small-molecule fragments, identifying approximately 50,000 interactions across 2,500 proteins, many of which previously had no known ligands. This extensive dataset allowed the creation of a machine learning model that predicts interactions based on fragment properties, enhancing our understanding of how these interactions work within cells. The findings and tools have been made accessible online, providing a valuable resource for future chemical biology research and ligand discovery.
A novel deconvolution method has been developed to analyze bulk proteome data by leveraging matched bulk transcriptome and proteome data, without the need for a proteomics reference panel. This approach, which integrates tissue-matched transcriptomic and proteomic data, allows for the identification of proteins that contribute to cellular heterogeneity. It has shown robust and accurate cell abundance quantification across diverse datasets including human brain and breast cancer tissues, enabling effective downstream applications like cell-specific protein Quantitative Trait Loci (cspQTL) mapping. The tool implementing this method, named MICSQTL, also supports integrative visualization of multi-omics data and is available for use.
Research highlights that sensory perception of food triggers mitochondrial fragmentation in the liver, mediated by the phosphorylation of mitochondrial fission factor via AKT kinase, influenced by hypothalamic neurons. This process is critical for adapting liver metabolism to anticipated changes in nutrient availability, impacting insulin’s role in regulating blood sugar. Disrupting this pathway could alter metabolic responses and affect glucose production in the liver, underscoring the complexity of metabolic regulation tied to diet.
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Experimental Medicine , Faculty of Medicine, UBC, Vancouver | Medical Content Writing
1 个月Exciting newsletter content! How do you see the integration of AI in proteomics shaping future research and innovation? https://lnkd.in/guWiXGVC