bims-mesote 2025-02-23 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2025–02–23
eight papers selected by
Laura Mannarino, Humanitas Research

M2-like tumor-associated macrophages may promote tumor progression in malignant pleural mesothelioma.
The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes.
DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy.
Telomeres and telomerase in mesothelioma: Pathophysiology, biomarkers and emerging therapeutic strategies (Review).
miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma.
Potential utility of miRNAs derived from pleural fluid extracellular vesicles to differentiate between benign and malignant pleural effusions.
CD276 as a critical independent biomarker and immune checkpoint inhibitor target in epithelioid mesothelioma-TCGA study.
Pleural infection: controversies on the therapeutic strategies.

Transl Oncol. 2025 Feb 20. pii: S1936-5233(25)00055-5. [Epub ahead of print]54 102324

M2-like tumor-associated macrophages may promote tumor progression in malignant pleural mesothelioma.

Tetsuya Fukui, Ryota Sumitomo, Toshi Menju, Masashi Kobayashi, Hiroaki Sakai, Hiroshi Date.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with an unfavorable prognosis. Asbestos-activated macrophages may contribute to both oncogenesis and progression of MPM. This study aimed to clarify the biological and clinical significance of M2-like tumor-associated macrophages (TAMs) in MPM.
METHODS: This retrospective study included 101 MPM patients who were diagnosed and started treatment between 1998 and 2010. The distribution of M2-like TAMs in the intratumoral and peritumoral regions was evaluated by immunohistochemistry using CD163 staining. Tumor proliferation was evaluated by Ki-67 staining.
RESULTS: Intratumoral M2-like TAM density was significantly correlated with the pretreatment C-reactive protein level (r = 0.283, P = 0.004) and Ki-67 proliferation index (r = 0.498, P < 0.001). Peritumoral M2-like TAM density was also significantly correlated with the pretreatment C-reactive protein level (r = 0.255, P = 0.010) and Ki-67 proliferation index (r = 0.435, P < 0.001). Additionally, intratumoral M2-like TAM density was associated with histological subtype (P < 0.001), with higher densities observed in sarcomatoid tumors compared to epithelioid tumors. The overall survival rate was significantly worse in the intratumoral and peritumoral M2-like TAM-high groups (P = 0.044 and P = 0.046, respectively), particularly in patients with advanced-stage MPM. Multivariable analysis identified peritumoral M2-like TAM status (hazard ratio = 1.700, 95 % confidence interval: 1.034-2.796, P = 0.037), clinical stage, and histology as significant prognostic factors for overall survival.
CONCLUSIONS: During MPM progression, M2-like TAMs may induce tumor cell proliferation and aggressiveness, contributing to the poor prognosis in MPM patients.

Keywords:  Histology; Mesothelioma; Progression; Tumor cell proliferation; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.tranon.2025.102324
J Transl Med. 2025 Feb 20. 23(1): 208

The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes.

Federica Torricelli, Filomena Spada, Cynthia Bishop, Katrina Todd, Daisuke Nonaka, Nedyalko Petrov, Manuela Terranova Barberio, Alan G Ramsay, Richard Ellis, Alessia Ciarrocchi, Benedetta Apollonio, Andrea Billè.

   BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options. To improve patients management and treatment, more precise stratification strategies are needed. This study aimed to characterize the phenogenomic landscapes of MPM and to understand their influence on patients clinical outcomes.
METHODS: We conducted a phenogenomic analysis on 22 MPM patients using two high throughput approaches: imaging mass cytometry (IMC) with whole exome sequencing (WES). Resulting profiles were addressed for their clinical relevance to predict patients prognosis.
RESULTS: IMC revealed a highly heterogeneous tumor microenvironment (TME) with distinct tumor cell subpopulations. Notably, we identified a novel sarcomatoid-like cellular cluster associated with poor prognosis. The TME was also infiltrated with immune cells including macrophages and CD4+ T lymphocytes, that were more abundant in patients with favorable clinical outcomes. WES identified a complex genomic landscape with limited prognostic value for individual genetic alterations. However, tumor mutational burden (TMB) emerged as a potential predictive biomarker, inversely correlating with immune cell infiltration, particularly macrophages and CD4+ T lymphocytes.
CONCLUSIONS: Our findings underscore the intricate interplay between the tumor genome, TME composition, and clinical outcomes in MPM. These data support the potential of integrating genomic and TME profiling to develop more precise patient stratification strategies and potentially optimize therapeutic approaches, including immunotherapy.

Keywords:  Imaging mass cytometry; Mesothelioma; Whole genome sequencing

DOI:  https://doi.org/10.1186/s12967-025-06193-z
J Exp Clin Cancer Res. 2025 Feb 18. 44(1): 58

DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy.

EPigenetic Immune-oncology Consortium Airc (EPICA) investigators

   BACKGROUND: Co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival (OS) over conventional chemotherapy. The analysis by tumor histotype demonstrated greater efficacy of ICI therapy compared to standard chemotherapy in non-epithelioid (non-E) vs. epithelioid (E) PM, although some E PM patients also benefit from ICI treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape, along with its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients.
METHODS: The methylome profile (EPIC array) of distinct E (n = 5) and non-E (n = 9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed (DE) and differentially methylated (DM) were then selected for gene ontology analysis.
RESULTS: The CIMP index stratified PM cell lines into two distinct classes, CIMP (hyper-methylated; n = 7) and LOW (hypo-methylated; n = 7), regardless of their E or non-E histotype. Integrated methylome and transcriptome analyses revealed that CIMP PM cells exhibited a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells.
CONCLUSION: The study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state highlights its potential for evaluation in phase I/II clinical trials investigating the efficacy of epigenetic-based ICI combinations to reverse cancer immune resistance mechanisms.

Keywords:  DNA methylation; Epigenetic; Guadecitabine; Immunotherapy; Pleural mesothelioma

DOI:  https://doi.org/10.1186/s13046-025-03310-0
Int J Oncol. 2025 Mar;pii: 23. [Epub ahead of print]66(3):

Telomeres and telomerase in mesothelioma: Pathophysiology, biomarkers and emerging therapeutic strategies (Review).

Dimitrios Andreikos, Demetrios A Spandidos, Vasiliki Epameinondas Georgakopoulou.

  Malignant mesothelioma (MM) is a rare but aggressive cancer linked to asbestos exposure and characterized by advanced‑stage disease at presentation. Despite advances in treatment, prognosis remains abysmal, highlighting the imperative for the development of novel biomarkers and treatment approaches. Telomere biology plays a pivotal role in the tumorigenic process and has emerged as a key area in oncology research. Short telomeres have been associated with genomic instability, and substantially shorter telomere length (TL) has been identified in MM, showcasing the potential of TL in risk assessment, early detection, and disease progression monitoring. MM predominantly maintains TL through telomerase activity (TA), which in research has been identified in >90% of MM cases, underscoring the potential of TA as a biomarker in MM. Telomerase reverse transcriptase (TERT) polymorphisms may serve as valuable biomarkers, with research identifying associations between single nucleotide polymorphisms (SNPs) and the risk and prognosis of MM. Additionally, TERT promoter mutations have been associated with poor prognosis and advanced‑stage disease, with the non‑canonical functions of TERT hypothesized to contribute to the development of MM. TERT promoter mutations occur in ~12% of MM cases; C228T, C250T and A161C are the most common, while the distribution and frequency differ depending on histological subtype. Research reveals the promise of the various approaches therapeutically targeting telomerase, with favorable results in pre‑clinical models and inconclusive findings in clinical trials. The present review examines the role of telomere biology in MM and its implications in diagnosis, prognosis, and therapy.

Keywords:  biology; cancer; mesothelioma; telomerase; telomeres

DOI:  https://doi.org/10.3892/ijo.2025.5729
J Exp Clin Cancer Res. 2025 Feb 22. 44(1): 65

miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma.

Miriam Piccioni, Francesco Di Meo, Anna Valentino, Virginia Campani, Maddalena Arigoni, Mirella Tanori, Mariateresa Mancuso, Rossana Cuciniello, Marco Tomasetti, Federica Monaco, Gaia Goteri, Enrico P Spugnini, Raffaele A Calogero, Giuseppe De Rosa, Gianfranco Peluso, Alfonso Baldi, Stefania Crispi.

   BACKGROUND: Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.
METHODS: miRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples.
RESULTS: In vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin.
CONCLUSIONS: Our study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM.

Keywords:  Apoptosis; LNPs; Mesothelioma; Tumor growth inhibition; miRNA-503 inhibition

DOI:  https://doi.org/10.1186/s13046-025-03283-0
Transl Lung Cancer Res. 2025 Jan 24. 14(1): 124-138

Potential utility of miRNAs derived from pleural fluid extracellular vesicles to differentiate between benign and malignant pleural effusions.

Tian Mun Chee, Caeli J Zahra, Kwun M Fong, Ian A Yang, Rayleen V Bowman.

   Background: Cytological examination is of suboptimal sensitivity but high specificity for the diagnosis of malignant pleural effusions (MPEs). Pleural fluid extracellular vesicles (PFEVs) are enriched with disease-specific microRNAs (miRNAs) which may improve the diagnostic yield for MPE. Our previous study demonstrated the feasibility of isolating miRNAs from PFEVs and profiling PFEV miRNAs by Nanostring nCounter® Human v3 miRNA expression assay. Here, we interrogated in a small cohort to evaluate the diagnostic potential of PFEV miRNAs to differentiate between benign pleural effusion and MPE.
Methods: Extracellular vesicles (EVs) from pleural fluids were isolated by two sequential ultracentrifugation steps. PFEVs were extracted and characterised by western blotting analysis, particle analysis by tunable resistive pulse sensing (TRPS) technology, and transmission electron microscopy (TEM). Total RNAs (including miRNAs) were extracted from PFEVs and profiled by the Nanostring nCounter® 827 probe miRNA expression assay. Differential expression analysis of the miRNA expression assays on PFEV samples was performed using the Bioconductor DESeq2 package.
Results: EVs from pleural fluids were evident by staining of positive EV-associated protein markers, particle size distribution within the expected parameters, and the cup-shaped morphology by TEM. Employing Nanostring nCounter® Human v3 miRNA expression assay, this proof-of-principle study demonstrated PFEV miRNAs were differentially expressed between benign effusions and malignant effusions [malignant pleural mesothelioma (MPM) or lung adenocarcinoma metastatic to pleura (metLUAD)]. The expression of six miRNAs (hsa-miR-1246, hsa-miR-136-5p, hsa-miR-141-3p, hsa-miR-145-5p, hsa-miR-200c-3p, and hsa-miR-9-5p) significantly differed between benign and malignant effusions, or between MPM and metLUAD, at adjusted P<0.05 and log2fold change ≥1.0.
Conclusions: The miRNAs identified from this study could be interrogated further for their utility as a single biomarker candidate or to be tested simultaneously in a panel to complement pleural effusion diagnostics. PFEV miRNAs represent a novel bioresource with potential to aid in the diagnosis of pleural effusions. Larger prospective studies are needed to confirm their diagnostic utility.

Keywords:  Pleural fluid; extracellular vesicles (EVs); lung cancer; mesothelioma; microRNA (miRNA)

DOI:  https://doi.org/10.21037/tlcr-24-945
J Thorac Dis. 2025 Jan 24. 17(1): 109-120

CD276 as a critical independent biomarker and immune checkpoint inhibitor target in epithelioid mesothelioma-TCGA study.

Yuko Aoki, Ken Arimura, Kenzo Hiroshima, Yasuto Sato, Mitsuko Kondo, Etsuko Tagaya.

   Background: CD276 is an immune checkpoint, and immune checkpoint inhibitors (ICIs) targeting CD276 have been tested against various cancers. However, the precise role of CD276 in mesothelioma subtypes is unknown. This study aimed to reveal the prognostic significance of CD276 in various cancers and explore CD276 as a target for ICIs in different mesothelioma subtypes.
Methods: We evaluated data from The Cancer Genome Atlas (TCGA) database retrospectively. The Wilcoxon rank-sum test was used to assess CD276 mRNA expression between cancer tissues and the adjacent normal tissues in the context of various cancers. The study involved 86 patients with mesothelioma. The mean number of patients was set as the cutoff value for comparing CD276 mRNA expression. The overall survival (OS) of patients with each mesothelioma subtype was estimated using the Kaplan-Meier method with CD276 mRNA expression. The factors affecting the correlation between OS and high/low CD276 expression in combination with/without a current existing molecular targets of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and vascular endothelial growth factor A (VEGFA) were assessed using a multivariate Cox proportional hazards model. The correlation between the mRNA expression of CD276 and expression of gene markers of tumor-infiltrating immune cells and those of different pathways was evaluated using Spearman's correlation. The factors affecting correlations of CD276 mRNA expression were confirmed using a multivariate linear regression model.
Results: Upregulated CD276 mRNA expression was associated with a poor prognosis in various cancers, including epithelioid mesothelioma. The multivariate Cox proportional hazards model demonstrated that upregulated CD276 mRNA expression indicated the worst prognosis, including the combination of CD276 and PD-1, CTLA4, and VEGFA. In addition, using a multivariate linear regression model, CD276 mRNA expression was found to correlate with multiple glycolytic pathway mRNAs in epithelioid mesothelioma, especially PKM2.
Conclusions: CD276 is an independent prognostic biomarker in patients with epithelioid mesothelioma. It is associated with the glycolytic pathway and may contribute to ATP generation in epithelioid mesothelioma. CD276 inhibitors might contribute to better prognosis in patients with epithelioid mesothelioma.

Keywords:  B7-H3/CD276; The Cancer Genome Atlas (TCGA); epithelioid mesothelioma; immune checkpoint inhibitor (ICI); novel prognostic biomarker

DOI:  https://doi.org/10.21037/jtd-24-1598
Curr Opin Pulm Med. 2025 Feb 18.

Pleural infection: controversies on the therapeutic strategies.

Ken K P Chan, Estee P M Lau, Y C Gary Lee.

PURPOSE OF REVIEW: Management of pleural infection remains heterogeneous worldwide. This review highlights current controversies in therapeutic strategies for pleural infection, focusing particularly on recent studies and their implications.
RECENT FINDINGS: The introduction of intrapleural therapy combining alteplase [a tissue plasminogen activator (tPA)] and deoxyribonuclease (DNase) has revolutionized treatment practices, though the optimal delivery and dosing regimen is an area of active investigation. Variations to simplify administration protocols and/or to lower the required drug doses have been published. Most were exploratory studies, but the variations showed maintained therapeutic efficacy.Whether intrapleural alteplase/DNase or video-assisted thoracoscopic surgery (VATS) is superior is a topic of debate. Retrospective comparative analyses between the two revealed no clear benefits on all-cause mortality from either approach. Pilot randomized trials have been published and further full-scale, head-to-head trials are underway.
SUMMARY: Effective management of pleural infection involves adequate pleural drainage and appropriate antibiotic use. This review outlines the current evidence (and its limitations) and highlights knowledge gaps in optimizing the therapeutic strategies.

DOI: https://doi.org/10.1097/MCP.0000000000001157