bims-mesote 2025-08-17 papers

Issue of 2025–08–17
six papers selected by
Laura Mannarino, Humanitas Research

Transl Lung Cancer Res. 2025 Jul 31. 14(7): 2611-2625

Pleural mesothelioma patients and ex-exposed asbestos workers are immunologically poor responders to oncogenic Merkel cell polyomavirus.

Chiara Mazziotta, Carmen Lanzillotti, Christian Felice Cervellera, Giada Badiale, Roberta Libener, Antonio Maconi, Elisabetta Casalone, Alessandra Allione, Giuseppe Matullo, Manlio Mencoboni, Ilaria Bononi, Fernanda Martini, John Charles Rotondo, Mauro Tognon.

Background: Pleural mesothelioma (PM) is an aggressive tumor of the serous cavities primarily caused by the inhalation of asbestos, a carcinogenic and immunomodulatory mineral. Other factors, such as oncogenic viruses, might be involved in PM onset. Merkel cell polyomavirus (MCPyV) is a ubiquitous oncogenic DNA virus whose increased activity has been documented in conditions of immunosuppression. In this study, we aimed to investigate the immunological response to MCPyV in PM patients and workers ex-exposed to asbestos (WEA).
Methods: MCPyV serology was investigated herein in sera from 108 PM patients, 102 WEA, and 110 healthy subjects (HS). Total serum immunoglobulin G (IgG) levels were evaluated. The presence of MCPyV DNA and viral protein (VP)1 and large T (LT) messenger RNAs (mRNAs) was evaluated by droplet-digital polymerase chain reaction (ddPCR)/quantitative polymerase chain reaction (qPCR) in 50 tumor specimens from PM patients unrelated to PM serum donors.
Results: Reduced serum anti-MCPyV IgG rates and optical densities (ODs) were detected in PM (26.9% and 0.08-0.09) and WEA (27.5% and 0.08-0.09) compared to HS (60.9% and 0.16-0.33) (P<0.001), while the mean total IgG concentrations were similar among groups (4.3-5.7 mg/mL) (P>0.05). Biphasic PM histotype exhibited the lowest MCPyV IgG levels. WEAs with the highest asbestos exposure had the lowest rate and ODs of serum anti-MCPyV IgGs (5.6% and 0.074-0.083) in contrast to WEA (44.4% and 0.083-0.096) with lower exposure. Spearman analyses revealed an inverse correlation between ODs and both cumulative asbestos exposure and years of asbestos exposure (P<0.05), while a direct correlation was detected between years since last exposure and ODs (P=0.02). MCPyV DNA was detected in 32% of PM specimens with a mean viral DNA load of 0.39±0.2 copy/cell. VP1 mRNA was detected in all MCPyV DNA-positive PMs, while 69% of these specimens tested LT mRNA-positive.
Conclusions: Our study provides the first evidence that PM and WEA may experience a specific impairment of their immune response to MCPyV. This might possibly depend on the immunomodulatory effect of asbestos, a well-known immunosuppressive mineral.

Keywords: Merkel cell polyomavirus (MCPyV); asbestos; immunological response; immunology; pleural mesothelioma (PM)

DOI: https://doi.org/10.21037/tlcr-2025-198

Oncogenesis. 2025 Aug 11. 14(1): 28

Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma.

Yantang Lin, Christelle Dubey, Tereza Losmanova, Samuel Oevgü Yasmin, Jean-Louis Reymond, Ren-Wang Peng, Haibin Deng, Patrick Dorn, Thomas Michael Marti.

Pleural mesothelioma (PM) is an aggressive, asbestos-linked cancer with limited treatment options and a poor prognosis. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate, and its silencing reduces mitochondrial metabolism, particularly nucleotide synthesis. However, whether and a role of LDHB in PM is unclear. This study aimed to investigate the effects of silencing LDHB in PM cells and their response to chemotherapy. LDHB was silenced using siRNA transfection and inducible shRNA constructs. Proliferation, colony formation, and cell viability were assessed, while DNA damage was analyzed through ɣH2AX levels. Compared to normal mesothelial cells, LDHB was highly expressed in PM cell lines. LDHB inhibition significantly reduced proliferation, cell viability, and colony formation, indicating its crucial role in PM cells. Additionally, LDHB silencing significantly increased nuclear DNA damage accumulation as indicated by elevated ɣH2AX levels, which was reversed by nucleotide supplementation. In vivo, LDHB inhibition reduced tumor growth and enhanced cisplatin's therapeutic efficacy. LDHB silencing increased ɣH2AX levels, which were further elevated with cisplatin treatment. Our results highlight LDHB as a novel therapeutic target in PM, where its inhibition induces DNA damage and improves the efficacy of cisplatin therapy.

DOI: https://doi.org/10.1038/s41389-025-00571-4

Lung Cancer. 2025 Aug 05. pii: S0169-5002(25)00571-9. [Epub ahead of print]207 108679

Single-cell RNA-sequencing as a potential approach for studying intratumor heterogeneity in pleural mesothelioma.

Ania Alay, Raúl Marín, Elisabet Aliagas, Mireia Gausachs, Max Ruiz-Gil, Ivan Macia, Amaia Ojanguren, Susana Padrones, Eduard Dorca, Jesús Brenes, Ramón Palmero, Víctor Moreno, Holger Heyn, David Cordero, Ernest Nadal, Xavier Solé.

Pleural mesothelioma (PM) is a rare and lethal cancer with limited treatment options. Intratumor heterogeneity (ITH) has been postulated as one of the reasons for the poor treatment response observed in most PM patients. In this regard, we aimed to characterize ITH in a multi-site tumor specimen using single-cell RNA-sequencing (scRNA-seq).
METHODS: Tumor cells from three distant biopsies (costal, diaphragmatic, and mediastinal) of an epithelioid PM were analyzed with scRNA-seq.
RESULTS: Three main cell states were identified in all regions: C1, stem-like; C2, epithelial-like; and C3, mesenchymal-like. C1 state was the most prominent globally, although it was less abundant in the mediastinal biopsy, compared to the other two studied regions. Trajectory analysis was suggestive of an epithelial-mesenchymal plasticity dynamic, including a stem-like intermediate state. Signatures of upregulated genes in each state (SigC1, SigC2, SigC3) were obtained and assessed in a large cohort of PM samples. Patients with tumors enriched in SigC3 were associated with worse survival and with reduced sensitivity to standard of care PM regimens. Additionally, SigC1 appeared to be potentially more sensitive to anti-angiogenic therapies.
CONCLUSIONS: This study highlights that scRNA-seq is useful to capture PM cellular and molecular heterogeneity and identifies gene-expression signatures with potential clinical relevance for future treatment tailoring.

Keywords: Pleural mesothelioma; epithelial-mesenchymal plasticity; epithelial-to-mesenchymal transition; gene expression signature; single-cell RNA-sequencing, tumor heterogeneity

DOI: https://doi.org/10.1016/j.lungcan.2025.108679

J Clin Med. 2025 Aug 04. pii: 5467. [Epub ahead of print]14(15):

A Promising Prognostic Indicator for Pleural Mesothelioma: Pan-Immuno-Inflammation Value.

Serkan Yaşar, Feride Yılmaz, Ömer Denizhan Tatar, Hasan Çağrı Yıldırım, Zafer Arık, Şuayib Yalçın, Mustafa Erman.

Background: Pleural mesothelioma (PM) is a type of cancer that is difficult to diagnose and treat. Patients may have vastly varying prognoses, and prognostic factors may help guide the clinical approach. As a recently identified biomarker, the pan-Immune-Inflammation-Value (PIV) is a simple, comprehensive, and peripheral blood cell-based biomarker. Methods: The present study represents a retrospective observational analysis carried out within a single-center setting. Ninety-five patients with PM stages I-IV were enrolled in the study. We analyzed the correlation between patients' demographic characteristics, clinicopathological factors such as histological subtypes, surgery status, tumor thickness, blood-based parameters, and treatment options with their prognoses. PIV was calculated by the following formula: (neutrophil count × monocyte count × platelet count)/lymphocyte count. Additionally, blood-based parameters were used to calculate the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII). Results: We categorized the patients into two groups, low PIV group (PIV ≤ 732.3) and high PIV group (PIV > 732.3) according to the determined cut-off value, which was defined as the median. It was revealed that high PIV was associated with poor survival outcomes. The median follow-up period was 15.8 months (interquartile range, IQR, 7.1 to 29.8 months). The median overall survival (OS) was significantly longer in patients in the low PIV group (median 29.8 months, 95% confidence interval (CI), 15.6 to 44) than the high PIV group (median 14.7 months, 95% CI, 10.8 to 18.6 p < 0.001). Furthermore, the study revealed that patients with low PIV, NLR, and SII values were more likely to be eligible for surgery and were diagnosed at earlier stages. Additionally, these markers were identified as potential predictors of disease-free survival (DFS) in the surgical cohort and of treatment response across the entire patient population. Conclusions: In addition to well-established clinical factors such as stage, histologic subtype, resectability, and Eastern Cooperative Oncology Group (ECOG) performance status (PS), PIV emerged as an independent and significant prognostic factor of overall survival (OS) in patients with PM. Moreover, PIV also demonstrated a remarkable independent prognostic value for disease-free survival (DFS) in this patient population. Additionally, some clues are provided for conditions such as treatment responses, staging, and suitability for surgery. As such, in this cohort, it has outperformed the other blood-based markers based on our findings. Given its ease of calculation and cost-effectiveness, PIV represents a promising and practical prognostic tool in the clinical management of pleural mesothelioma. It can be easily calculated using routinely available laboratory parameters for every cancer patient, requiring no additional cost or complex procedures, thus facilitating its integration into everyday clinical practice.

Keywords: pan-immune inflammation value; pleural mesothelioma; prognostic factors

DOI: https://doi.org/10.3390/jcm14155467

Glycoconj J. 2025 Aug 13.

Molecular expression of glycosaminoglycans modifies the plasticity of biphasic mesothelioma in favor of tumor progression.

Camila Machado Baldavira, Aline Nery Qualiotto, Tabatha Gutierrez Prieto, Sandra de Morais Fernezlian, Aline Assato, Marcelo Balancin, Teresa Takagaki, Alexandre Ab'Saber, Ana Paula Pereira Velosa, Walcy Rosolia Teodoro, Vera Luiza Capelozzi.

The study aimed to verify whether the expression of glycosaminoglycans (GAGs) and proteoglycans (PGs) in the tumor matrix affects the plasticity of mesothelioma and its relationship with the phenotype, progression, and resistance to treatment of malignant mesothelioma (MM). As MM is highly aggressive, understanding the molecular mechanisms that regulate the abilities of tumor cells to alter their behaviors and shapes is essential to the development of new therapeutic strategies. To test this hypothesis, we studied 66 samples of human biphasic MM. The expression levels of the GAGs heparan sulfate (HS) and chondroitin sulfate (SC), as well as the PGs versican, biglycan, and perlecan were detected using immunohistochemistry, and their expression was quantified using semi-automated digital analysis. We found that the fusiform phenotype of MM cells was associated with higher expression levels of HS, versican, and biglycan (all P-values < 0.001) in the extracellular matrix. This suggests that the increase and eventual rapid turnover of cell membrane PGs resulted in a variation in shape from polygonal to fusiform phenotypes, whereas GAGs were associated with cell aggregation-thus indicating the distinct functions of different GAGs. Multivariate Cox regression analysis showed that non-surgical patients (hazard ratio [HR]: 4.03 (1.26-12.82); P = 0.02), whose tumors presented necrosis (P < 0.001), high HS expression (P = 0.02), and low biglycan expression (HR: 2.68 [1.16-6.18]; P = 0.02) had significantly worse overall survival rates. We concluded that the expression of GAGs and PGs in the ECM affects the plasticity of MM, modifies its phenotype, and facilitates both its progression and resistance to treatment.

Keywords: Glycosaminoglycans; Mesothelioma; Proteoglycans; Resistance; Tumor progression

DOI: https://doi.org/10.1007/s10719-025-10192-z

Cancer Epidemiol. 2025 Aug 08. pii: S1877-7821(25)00160-2. [Epub ahead of print]98 102900

Global trends, future projections, and epidemiological associations of Mesothelioma: A comprehensive analysis from 1980 to 2050.

Shanjie Luan, Yanqing Wang.

BACKGROUND: Malignant mesothelioma is a rare but aggressive cancer primarily caused by occupational asbestos exposure. This study aims to comprehensively assess global mesothelioma incidence and mortality trends, examine their associations with the Human Development Index (HDI), project future burden through 2050, and investigate epidemiological correlations with other malignancies.
METHODS: We extracted mesothelioma incidence and mortality data from GBD 2021 and GLOBOCAN 2022, covering 204 and 185 countries from 1980 to 2022, respectively. Temporal trends were analyzed using estimated annual percentage change (EAPC), while age-period-cohort (APC) modeling was applied in six high-HDI countries to assess generational burden shifts. Future projections were generated using age-stratified machine-learning models trained on historical data and validated against multiple forecasting methods. Additionally, mesothelioma's epidemiological associations with 27 other cancers were analyzed using linear and logistic regression.
RESULTS: Between 1990 and 2021, global mesothelioma incidence and mortality showed a modest decline (ASIR EAPC: -0.2 [95 % UI: -0.32 to -0.08]; ASDR EAPC: -0.23 [95 % UI: -0.3 to -0.16]). Males exhibited a significantly higher burden than females, with the UK and Australia reporting the highest incidence and mortality rates. A clear threshold effect of HDI was observed, with mesothelioma rates remaining stable below HDI 0.8 but rising sharply beyond this level. Additionally, mesothelioma demonstrated strong positive correlations with tracheobronchial lung cancer, ovarian cancer, and Hodgkin lymphoma, suggesting potential shared environmental and occupational risk factors.
CONCLUSIONS: Our findings provide the most up-to-date epidemiological insights into mesothelioma, highlighting its stable long-term burden, gender disparities, and socioeconomic influences.

Keywords: Cancer Burden Projection; Cancer Correlation; Epidemiology; Global Burden of Disease; Machine Learning; Mesothelioma

DOI: https://doi.org/10.1016/j.canep.2025.102900