WCLC 2025 - Posters & ePosters-P3.03.05 Proteomic Analysis of Pleural Mesothelioma

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This study presents a comprehensive proteomic analysis of pleural mesothelioma (PM), a cancer characterized by a highly immunosuppressive tumor microenvironment (TME) and poorly understood metabolic alterations. Using iMPAQT, a high-throughput targeted proteomics technique enabling absolute quantification of approximately 1,000 metabolic enzymes, the researchers analyzed tumor specimens from four PM patients alongside three matched normal pleural tissue samples. <br /><br />The global proteomic profiling revealed distinct enzyme expression patterns, with 297 enzymes significantly upregulated in PM tumors compared to normal pleura. Pathway analysis highlighted the upregulation of key metabolic pathways including pyrimidine nucleotide biosynthesis, folate metabolism, heme synthesis, and biosynthesis of cofactors. Notably, enzymes involved in de novo pyrimidine synthesis (such as CAD and UMPS) were markedly elevated.<br /><br />Survival analysis using data from The Cancer Genome Atlas (TCGA) demonstrated that high expression levels of CAD correlate with poorer overall survival in PM patients, suggesting that pyrimidine metabolism enzymes may serve as prognostic biomarkers. The study discusses the immunosuppressive implications of altered nucleotide metabolism, as catabolic products like adenosine can inhibit anti-tumor immune responses.<br /><br />Overall, the findings elucidate profound metabolic rewiring in PM, with pyrimidine metabolism emerging as a critical vulnerability. The authors propose that targeting pyrimidine biosynthetic pathways may represent a rational therapeutic approach. Furthermore, they suggest combining metabolic inhibitors with immune checkpoint blockade could potentially overcome tumor-induced immunosuppression, warranting further investigation into dual-modality treatments for PM. This study advances understanding of PM biology and identifies promising avenues for developing targeted therapies against its unique metabolic dependencies.

Asset Subtitle

Tetsuzo Tagawa

Meta Tag

Speaker Tetsuzo Tagawa

Topic Tumor Biology – Translational Biology

Keywords

pleural mesothelioma

proteomic analysis

tumor microenvironment

metabolic alterations

iMPAQT

pyrimidine nucleotide biosynthesis

CAD enzyme

prognostic biomarkers

immunosuppression

targeted therapies