bims-mesote 2023-02-12 papers

Issue of 2023–02–12
five papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2023 Jan 19. pii: 641. [Epub ahead of print]15(3):

Identification of Highly Sensitive Pleural Effusion Protein Biomarkers for Malignant Pleural Mesothelioma by Affinity-Based Quantitative Proteomics.

Nicolai B Palstrøm, Martin Overgaard, Peter Licht, Hans C Beck.

Malignant pleural mesothelioma (MPM) is an asbestos-associated, highly aggressive cancer characterized by late-stage diagnosis and poor prognosis. Gold standards for diagnosis are pleural biopsy and cytology of pleural effusion (PE), both of which are limited by low sensitivity and markedly inter-observer variations. Therefore, the assessment of PE biomarkers is considered a viable and objective diagnostic tool for MPM diagnosis. We applied a novel affinity-enrichment mass spectrometry-based proteomics method for explorative analysis of pleural effusions from a prospective cohort of 84 patients referred for thoracoscopy due to clinical suspicion of MPM. Protein biomarkers with a high capability to discriminate MPM from non-MPM patients were identified, and a Random Forest algorithm was applied for building classification models. Immunohistology of pleural biopsies confirmed MPM in 40 patients and ruled out MPM in 44 patients. Proteomic analysis of pleural effusions identified panels of proteins with excellent diagnostic properties (90-100% sensitivities, 89-98% specificities, and AUC 0.97-0.99) depending on the specific protein combination. Diagnostic proteins associated with cancer growth included galactin-3 binding protein, testican-2, haptoglobin, Beta ig-h3, and protein AMBP. Moreover, we also confirmed previously reported diagnostic accuracies of the MPM markers fibulin-3 and mesothelin measured by two complementary mass spectrometry-based methods. In conclusion, a novel affinity-enrichment mass spectrometry-based proteomics identified panels of proteins in pleural effusion with extraordinary diagnostic accuracies, which are described here for the first time as biomarkers for MPM.

Keywords: fibulin-3; malignant mesothelioma; mesothelin; pleural effusion biomarkers; proteomics

DOI: https://doi.org/10.3390/cancers15030641

Cell Death Discov. 2023 Feb 10. 9(1): 55

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

Haitang Yang, Yanyun Gao, Duo Xu, Ke Xu, Shun-Qing Liang, Zhang Yang, Amina Scherz, Sean R R Hall, Stefan Forster, Sabina Berezowska, Feng Yao, Adrian F Ochsenbein, Thomas M Marti, Gregor J Kocher, Ralph A Schmid, Patrick Dorn, Ren-Wang Peng.

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.

DOI: https://doi.org/10.1038/s41420-023-01307-2

Int J Mol Sci. 2023 Feb 02. pii: 2874. [Epub ahead of print]24(3):

The Pattern of RNA Editing Changes in Pleural Mesothelioma upon Epithelial-Mesenchymal Transition.

Emanuela Felley-Bosco, Weihong Qi, Didier Jean, Clément Meiller, Hubert Rehrauer.

Pleural mesothelioma (PM) is a cancer where epithelioid, biphasic and sarcomatoid histotypes are observed. Sarcomatoid PM is characterized by mesenchymal features. Multi-omics have been used to characterize the epithelial-to-mesenchymal (EMT) phenotype at the molecular level. We contribute to this effort by including the analysis of RNA editing. We extracted samples with the highest vs. lowest Epithelial score from two PM cohorts and observed increased RNA editing in introns and decreased RNA editing in 3'UTR upon EMT. The same was observed in primary PM primary cultures stratified by transcriptomics analysis into two groups, one of them enriched with mesenchymal features. Our data demonstrate that, as has been observed in other cancer types, RNA editing associates to EMT phenotype in PM.

Keywords: RNA editing; epithelial-to-mesenchymal transition; pleural mesothelioma

DOI: https://doi.org/10.3390/ijms24032874

Eur Respir Rev. 2023 Mar 31. pii: 220174. [Epub ahead of print]32(167):

Rare thoracic cancers: a comprehensive overview of diagnosis and management of small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours.

ERN-LUNG Core Network Mesothelioma

Despite the progress in outcomes seen with immunotherapy in various malignancies, including nonsmall cell lung cancer, the benefits are less in small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours. New effective treatment options are needed, guided via more in-depth insights into the pathophysiology of these rare malignancies. This review comprehensively presents an overview of the clinical presentation, diagnostic tools, staging systems, pathophysiology and treatment options for these rare thoracic cancers. In addition, opportunities for further improvement of therapies are discussed.

DOI: https://doi.org/10.1183/16000617.0174-2022

Occup Environ Med. 2023 Feb 08. pii: oemed-2022-108669. [Epub ahead of print]

Incidence and mortality from malignant mesothelioma 1982-2020 and relationship with asbestos exposure: the Australian Mesothelioma Registry.

Karen Walker-Bone, Geza Benke, Ewan MacFarlane, S Klebe, Ken Takahashi, Fraser Brims, Malcolm Ross Sim, Tim R Driscoll.

OBJECTIVES: Malignant mesothelioma is an uncommon cancer associated with asbestos exposure, predominantly occupational. Asbestos has been banned in Australia since 2003 but mesothelioma has a long latency and incident cases continue to present. The Australian Mesothelioma Registry was incepted to collect systematic data about incidence and mortality alongside asbestos exposure.
METHODS: Benefiting from the Australian national system of cancer notification, all incident cases of mesothelioma in all states and territories are fast-tracked and notified regularly. Notified patients are contacted asking for consent to collect exposure information, initially by postal questionnaire and subsequently by telephone interview. Age-standardised annual incidence rates and mortality rates were calculated. Asbestos exposure was categorised as occupational, non-occupational, neither or, both; and as low, or high, probability of exposure.
RESULTS: Mesothelioma incidence appears to have peaked. The age-standardised incidence rates have declined steadily since the early 2000s (peaking in males at 5.9/100 000 and in all-persons at 3.2/100 000), driven by rates in males, who comprise the majority of diagnosed cases. Rates in women have remained fairly stable since that time. Age-standardised mortality rates have followed similar trends. Mesothelioma remains the most common in those aged over 80 years. Nearly all (94%) cases were linked with asbestos exposure (78% occupational in men; 6.8% in women).
CONCLUSIONS: With effective control of occupational asbestos use, the decline in age-standardised incidence and death rates has occurred. Incidence rates among women, in whom occupational asbestos exposure is rarely detectable, remain unchanged, pointing to the role of household and /or environmental asbestos exposure.

Keywords: asbestos; mesothelioma; mortality; occupational health

DOI: https://doi.org/10.1136/oemed-2022-108669