bims-mesote Biomed News
on Mesothelioma
Issue of 2025–09–07
two papers selected by
Laura Mannarino, Humanitas Research
  1. Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma.
  2. CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma.
  1. Br J Cancer. 2025 Sep 04.
    Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma.
    Karin Schelch, Nadine Maach, Muhammad Hashim, Benjamin Zitta, Dominik Kirchhofer, Gerald Timelthaler, Anna Solta, Dominik Emminger, Verena Kopatz, Mir A Hoda, Walter Berger, Clemens Aigner, Balazs Dome, Glen Reid, Michael Grusch.
       BACKGROUND: The cold-shock domain protein YB-1 is overexpressed in pleural mesothelioma (PM) and was shown to contribute to increased cell migration and platinum resistance.
    METHODS: Phosphorylation of YB-1 at position serine 102 was analysed by immunohistochemistry, immunofluorescence and immunoblotting in PM tissue specimens and cell lines. Intracellular localisation experiments involved immunoblotting, transfection of fluorescent protein-tagged YB-1 and confocal imaging. YB-1 phosphorylation was inhibited with the RSK inhibitors BI-D1870 and LJH685. Effects of inhibition alone and in combination with radiation or cisplatin treatment were analysed by cell viability assays, clonogenic assays and videomicroscopy-based migration and cell fate map analyses.
    RESULTS: YB-1 phosphorylated at serine 102 is present in PM cell lines and tissue. Inhibition of phosphorylation with BI-D1870 reduced YB-1 localisation in the cell nucleus and led to reduced cell viability, clonogenicity, migration and disrupted cell division. Moreover, exposure to BI-D1870 increased the effect of radiation and cisplatin treatment with additive to synergistic effects in PM cell lines and primary cultures.
    CONCLUSIONS: The serine 102 phosphorylated form of YB-1 contributes to the malignant phenotype of PM. Inhibition of YB-1 phosphorylation warrants further exploration as part of treatment strategies for this devastating disease.
    DOI:  https://doi.org/10.1038/s41416-025-03177-0
  2. J Exp Clin Cancer Res. 2025 Aug 28. 44(1): 256
    CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma.
    Federica Torricelli, Benedetta Donati, Veronica Manicardi, Mila Gugnoni, Francesca Reggiani, Gloria Manzotti, Pierluigi Di Chiaro, Cristian Ascione, Simonetta Piana, Riccardo Valli, Roberto Piro, Massimiliano Paci, Nicola Facciolongo, Filippo Lococo, Alessia Ciarrocchi.
       INTRODUCTION: Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.
    METHODS: A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.
    RESULTS: CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.
    CONCLUSION: These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.
    Keywords:  CDKN2A; Diffuse pleural mesothelioma; Genetic alteration; Immunotherapy; Tumor immune microenvironment
    DOI:  https://doi.org/10.1186/s13046-025-03522-4
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