bims-mesote 2025-03-30 papers

Issue of 2025–03–30
four papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2025 Mar 14. pii: 979. [Epub ahead of print]17(6):

An Overview of Cellular and Molecular Determinants Regulating Chemoresistance in Pleural Mesothelioma.

Lourdes Cortes-Dericks, Domenico Galetta.

Malignant pleural mesothelioma (PM) is a highly aggressive disease of the lung pleura associated with poor prognosis. Despite advances in improving the clinical management of this malignancy, there is no effective chemotherapy for refractory or relapsing PM. The acquisition of resistance to standard and targeted therapy in this disease is a foremost concern; therefore, a deeper understanding of the complex factors surrounding the emergence of drug resistance is deemed necessary. In this review, we will present broad insights into various cellular and molecular concepts, accounting for the recalcitrance of PM to chemotherapy, including signaling networks regulating drug tolerance, drug resistance-associated proteins, genes, and miRNAs, as well as the critical role of cancer stem cells. Identification of the biological determinants and their associated mechanisms may provide a framework for the development of appropriate treatment.

Keywords: chemoresistance; drug resistance mechanisms; drug-resistant cancer stem cells; malignant pleural mesothelioma

DOI: https://doi.org/10.3390/cancers17060979

Cancer Gene Ther. 2025 Mar 22.

Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence.

Glen Reid, Marissa Williams, Yuen Yee Cheng, Kadir Sarun, Patrick Winata, Michaela B Kirschner, Nancy Mugridge, Jocelyn Weiss, Mark Molloy, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk.

MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.

DOI: https://doi.org/10.1038/s41417-025-00885-w

Ann Thorac Surg. 2025 Mar 24. pii: S0003-4975(25)00224-3. [Epub ahead of print]

Updated post-recurrence survival outcomes in patients undergoing pleurectomy/decortication for pleural mesothelioma: A retrospective study.

Akifumi Nakamura, Masaki Hashimoto, Ayumi Kuroda, Kyoshiro Takegahara, Akihiro Fukuda, Seiji Matsumoto, Nobuyuki Kondo, Takashi Kijima, Seiki Hasegawa, Soichiro Funaki.

BACKGROUND: Pleural mesothelioma remains a challenging disease with a high recurrence rate despite multimodality treatment. We previously described clinical outcomes associated with post-pleurectomy/decortication recurrence in pleural mesothelioma. In this study, we aimed to update these results using data from a larger, more recent cohort and to identify prognostic factors influencing post-recurrence survival after pleurectomy/decortication.
METHODS: We conducted a retrospective cohort study involving 251 patients who underwent neoadjuvant chemotherapy with platinum plus pemetrexed, followed by pleurectomy/decortication from January 2012 to December 2022. We calculated survival and recurrence rates using the Kaplan-Meier method and the log-rank test, respectively. Multivariable analysis with the Cox proportional hazards model was used to assess clinical factors related to post-recurrence survival.
RESULTS: Of the 251 patients, 190 (75.7%) experienced recurrence (median follow-up, 30.9 months). The 2-year recurrence-free and overall survival rates were 37.3% (median, 21.1 months) and 72.3% (median, 44.1 months), respectively. The 1-year post-recurrence survival rate was 60.6% (median, 18.0 months). Multivariable analysis revealed that post-recurrence treatment (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.071-0.22; P < 0.0001), local recurrence (HR, 0.45; 95% CI, 0.31-0.66; P < 0.0001), age at recurrence < 70 years (HR, 0.53; 95% CI, 0.37-0.76; P = 0.0007), and disease-free interval > 12 months (HR, 0.43; 95% CI, 0.28-0.65; P < 0.0001) were independent, favorable, and significant prognostic factors of post-recurrence survival.
CONCLUSIONS: Post-recurrence treatment, recurrence pattern, age at recurrence, and disease-free interval significantly influence post-recurrence survival, indicating favorable outcomes in patients undergoing pleurectomy/decortication.

DOI: https://doi.org/10.1016/j.athoracsur.2025.03.014

Cancer Immunol Immunother. 2025 Mar 25. 74(5): 158

DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma.

Huilin Zhang, Luanxue Yu, Yunqing Guo, Jiawei Ming, Zhenying Guo.

BACKGROUND: Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma's progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated.
METHODS: This study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis.
RESULTS: HLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C's effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showed significant enrichment of immune-related and inflammatory pathways in patients with high HLA-C expression.
CONCLUSION: HLA-C, regulated by DNA methylation, plays a central role in mesothelioma prognosis by modulating immune responses, inflammatory cytokines, blood cell populations, and metabolic processes within the TME. Our findings suggest that HLA-C could serve as both a prognostic biomarker and a potential therapeutic target for mesothelioma, offering new insights into the molecular mechanisms driving this aggressive cancer.

Keywords: DNA methylation; HLA-C; Mendelian randomization; Mesothelioma; Tumor microenvironment

DOI: https://doi.org/10.1007/s00262-025-04012-4