bims-mesote 2025-12-07 papers

Br J Radiol. 2025 Dec 03. pii: tqaf297. [Epub ahead of print]

Staging Pleural Mesothelioma Revitalised.

Malignant pleural mesothelioma (PM) is the most common primary tumour of the pleura. Accurate staging is essential for treatment selection and prognostication. The 9th edition of the TNM classification introduces validated, imaging-based updates to tumour (T), node (N), and metastasis (M) staging. This article explores the scientific rationale and clinical utility of TNM 9, with a focus on imaging techniques, automated tumour volume assessment, and future developments in imaging and artificial intelligence.

DOI: https://doi.org/10.1093/bjr/tqaf297

J Thorac Oncol. 2025 Nov 28. pii: S1556-0864(25)02937-5. [Epub ahead of print]

Multi-omics, histologic, and scRNA-seq profiling of pleural mesothelioma reveals negative prognosis associated with a novel uncommitted molecular phenotype.

INTRODUCTION: Multi-omics pleural mesothelioma (PM) studies have identified prognostic molecular subsets of PM histologic types: epithelioid (ePM), biphasic (bPM), and sarcomatoid (sPM) defined by relative tumor cell content. However, the underlying biology modulating survival remains unknown.
METHODS: Using 93 samples from 40 patients, we performed single-cell RNA-sequencing (scRNA-seq), bulk exome and RNA-sequencing, optical genome mapping, spatial transcriptomics, and histologic analyses to identify candidate drivers and prognostic biomarkers of malignant cell (MC) state.
RESULTS: We identified a novel uncommitted MC state enriched in bPM tumors. Using inferred copy number variants, we observed all three MC states within individual clones suggesting MC state is not clonally restricted. We identified TGF-β and GAS6-AXL signaling as candidate MC state drivers for further study. Finally, we validated two prognostic MC state immunohistochemistry biomarkers, MEST (uncommitted), and MSLN (epithelioid).
CONCLUSIONS: These multi-omic, scRNA-seq analyses of primary patient tissues provide new candidate drivers of MC state and novel biomarkers to improve patient stratification. Further experimental exploration and clinical validation of these findings may reveal new treatment strategies and refine current clinical decision-making in pleural mesothelioma.

Keywords: Pleural mesothelioma; single cell RNA-seq; tumor micro-environment

DOI: https://doi.org/10.1016/j.jtho.2025.11.019

Discov Oncol. 2025 Dec 04.

Immunotherapy for pleural mesothelioma: from innovation to the frontlines of core clinical questions.

Tatsuya Yoshida, Kozo Kuribayashi.

In August 2018, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) became the first in the world to approve immune checkpoint inhibitor (ICI) monotherapy with nivolumab for previously treated, unresectable, advanced, or recurrent pleural mesothelioma (PM), setting a global precedent. Subsequently, in October 2020, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab and ipilimumab (CheckMate 743 trial) as the first-line treatment for unresectable PM. This marked the first update to standard first-line therapy in approximately 15 years since the approval of cisplatin (CDDP) plus pemetrexed (PEM) based on the EMPHACIS trial in 2004. Most recently, in September 2024, the FDA approved pembrolizumab plus platinum and PEM (KEYNOTE-483 trial) as another first-line option for advanced or metastatic PM. These developments underscore the rapid evolution of systemic therapy for PM. However, several urgent clinical questions have emerged in real-world practice. This article aims to address these issues based on the latest evidence and expert insights.

DOI: https://doi.org/10.1007/s12672-025-04200-9

Int J Biol Markers. 2025 Dec;40(4): 254-265

Human lysine oxidase-like 3 high expression as a potential biomarker and association with poor prognosis in pleural mesothelioma.

Wen Mei, Shengjie Yang, Qunshan Fu, Bing He, Xiaomei Sun, Wei Xiong, Yepin Zhang, Liqin Zhou.

PurposeAlthough human lysine oxidase-like 3 (LOXL3) is associated with various cancers, its role in pleural mesothelioma (PM) remains uncharacterized. This study investigated the expression level and prognostic association of LOXL3 in PM.MethodsTissue specimens were collected from patients with PM. The expression levels of LOXL3 were assessed using immunohistochemistry, Western blot analysis, and quantitative reverse transcription PCR. The clinical correlation analysis was conducted using R software (version 3.6.3), incorporating data from both The Cancer Genome Atlas and Chuxiong cohorts. Univariate and multivariate Cox proportional hazards regression models alongside Kaplan-Meier survival curve analysis were performed to evaluate prognostic significance. Additionally, gene expression correlation studies between LOXL3 and other members of the LOX family were performed using the Gene Expression Profiling Interactive Analysis platform. Finally, Gene Set Enrichment Analysis was conducted to identify the signaling pathways associated with LOXL3.ResultsLOXL3 exhibited significant upregulation in both sarcomatoid and biphasic PM subtypes compared to the control samples. Clinico-pathological analysis revealed the correlations between LOXL3 expression levels and cancer type, and Wilms tumor protein 1 (WT-1) status. Cox regression analysis identified cancer type as an independent prognostic factor. Kaplan-Meier analysis demonstrated obviously poorer survival rates in cohorts with high LOXL3 expression. Notably, coordinated expression patterns were observed between LOXL3 and LOXL4. The protein expression level of LOXL3 exhibits a positive correlation with CD68, CD206, and programmed death-ligand 1 (PD-L1), with this correlation being particularly pronounced in sarcomatoid mesothelioma. Functional enrichment analysis indicated that high LOXL3 expression was primarily associated with pathways related to oxidative phosphorylation, late and early estrogen response, and adipogenesis.ConclusionLOXL3 is highly expressed in PM and associated with poor prognosis, and is involved in tumor immune evasion. The expression level of LOXL3 is correlated with cancer types and the expression level of WT-1. Cancer type is an independent prognostic factor for PM. LOXL3 expression is positively associated with LOXL4, and high LOXL3 expression is enriched in oxidative phosphorylation, estrogen response, and adipogenesis pathways, while the low-expression group is enriched in apoptosis, interleukin-2/signal transducer and activator of transcription 5, mammalian target of rapamycin complex 1, and transforming growth factor-β pathways. CD68, CD206, PD-L1, and LOXL3 may collaboratively contribute to the regulation of the PM microenvironment and are closely linked to the invasion and metastasis of PM. Therefore, LOXL3 can be used as both a prognostic marker and a potential therapeutic target for PM.

Keywords: biomarker; lysine oxidase-like 3; pleural mesothelioma; prognosis; signaling pathways

DOI: https://doi.org/10.1177/03936155251396145

J Thorac Oncol. 2025 Dec;pii: S1556-0864(25)00976-1. [Epub ahead of print]20(12): e134-e137

A Response to the Letter to the Editor: Refining Risk and Redefining Stage: Hidden Implications of BAP1-Mutant Mesothelioma Shiuan-Chih Chen, MD, PhD; Yuan-Ti Lee, MD, PhD.

Michele Carbone, Michael Minaai, Muaiad Kittaneh, Thomas Krausz, Markku M Miettinen, Qiang Pan Hammarström, Lennart Hammarström, Hassan Abolhassani, Ian Pagano, Ronghui Xu, Flavia Novelli, Giovanni Gaudino, Sandra Pastorino, Kavita Y Sarin, Robert T Ripley, Harvey I Pass, David S Schrump, Haining Yang.

DOI: https://doi.org/10.1016/j.jtho.2025.07.124

Mol Biomed. 2025 Dec 03. 6(1): 131

Decoding the role of mesothelin in tumor dynamics and targeted treatment innovations.

Roberto Silvestri, Emanuela Colucci, Margherita Piccardi, Stefano Landi, Federica Gemignani.

Mesothelin (MSLN) is among the most studied cancer-related antigens, and it is extensively studied as a therapeutic target for the treatment of various malignancies, including pleural mesothelioma, pancreatic ductal adenocarcinoma, and ovarian cancer. However, despite the development of many MSLN-targeting strategies, such as antibody-drug conjugates (ADC), bispecific antibodies, and CAR-T cells, clinical responses have remained limited, underscoring the need for a deeper understanding of MSLN biology. Over the past decades, many studies have highlighted a link between MSLN and cancer progression and its association with specific features within the tumor microenvironment (TME). More recently, mechanistic evidence has emerged showing the involvement of MSLN in the establishment of key malignant features, such as the epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase 7-mediated remodeling of the extracellular matrix (ECM). Furthermore, these studies also show a direct role for MSLN in the immunosuppressive polarization of the TME through the interaction with CD206 macrophage receptors (leading to an M2-like polarization) and by promoting the transition of mesothelial cells into specific cancer-associated fibroblasts (CAFs). This review synthesizes current evidence on MSLN transcriptional regulation and its functional implications in invasion, metastasis, and immune evasion. We also summarize ongoing therapeutic strategies targeting MSLN and discuss how TME-driven resistance mechanisms are shaping the next generation of MSLN-directed therapies. By integrating molecular insights with translational perspectives, this work provides a comprehensive overview of MSLN biology and its emerging therapeutic relevance in cancer.

Keywords: Bispecific antibodies; CAR-T cells; Mesothelin; Targeted therapy; Tumor microenvironment

DOI: https://doi.org/10.1186/s43556-025-00379-z