bims-mesote 2022-07-10 papers

Issue of 2022–07–10
five papers selected by
Laura Mannarino, Humanitas Research

Thorac Cancer. 2022 Jul 05.

A comprehensive study of alternative splicing in malignant pleural mesothelioma identifies potential therapeutic targets in a new cluster with poor survival.

Ming-Ming Shao, Xin Qiao, Qing-Yu Chen, Feng-Shuang Yi.

BACKGROUND: Malignant pleural mesothelioma (MPM) is one of the most aggressive tumors with few effective treatments worldwide. It has been suggested that alternative splicing at the transcriptome level plays an indispensable role in MPM.
METHODS: We analyzed the splicing profile of 84 MPM patients from the TCGA cohort by using seven typical splicing types. We classified MPM patients based on their splicing status and conducted a comprehensive analysis of the correlation between the splicing classification and clinical characteristics, genetic variation, pathway changes, immune heterogeneity, and potential therapeutic targets.
RESULTS: The expression of the alternative splicing regulator SRPK1 is significantly higher in MPM tissues than in normal tissues, and correlates with poor survival. SRPK1 deficiency promotes MPM cell apoptosis and inhibits cell migration in vitro. We divided the MPM patients into four clusters based on their splicing profile and identified two clusters associated with the shortest (cluster 3) and longest (cluster 4) survival time. We present the different gene signatures of each cluster that are related to survival and splicing. Comprehensive analysis of data from the GDSC and TCGA databases revealed that cluster 3 MPM patients could respond well to the small-molecule inhibitor CHIR-99021, a small-molecule inhibitor of GSK-3.
CONCLUSION: We performed unsupervised clustering of alternative splicing data from 84 MPM patients from the TCGA database and identified a cluster associated with the worst prognosis that was sensitive to a GSK-3 inhibitor.

Keywords: GSK-3 inhibitor; alternative splicing events; malignant pleural mesothelioma; targeted therapy

DOI: https://doi.org/10.1111/1759-7714.14564

Front Pharmacol. 2022 ;13 867907

Improved Survival and Quality of Life Through an Integrative, Multidisciplinary Oncological Approach: Pathophysiological Analysis of Four Clinical Cancer Cases and Review of the Literature.

M Berretta, A Morra, R Taibi, F Monari, N Maurea, M Ippolito, U Tirelli, F Fiorica, L Montella, G Facchini, V Quagliariello, M Montopoli.

Objectives: According to the National Cancer Institute, the integrative medicine (IM) approach to medical care combines standard medicine with complementary and alternative medicine practices that have proved safe and effective. Methods: We describe the clinical cases of four patients with malignant pleural mesothelioma (MPM), diffuse malignant peritoneal mesothelioma (DMPM), intrahepatic cholangiocarcinoma, and breast cancer (BC) who received supportive treatment (ST) according to an IM approach after the failure of standard cancer treatments or the appearance of serious adverse events caused by antiblastic chemotherapy. The critical role of complementary drugs in reducing the side effects of cancer treatments and normalizing the white cell count is especially apparent in the case of the patient with metastatic BC, who experienced prolonged neutropenia. Results: The IM approach was well-tolerated and had no adverse side effects. It improved the quality of life (QoL) of all patients and in two cases extended overall survival. Conclusion: The extended clinical and instrumental response to IM of the patients with malignant mesothelioma and the improved health-related QoL and good tolerance of the ST demonstrated in all cases support the value of this approach in patients whose cancer therapies have failed but who show a good performance status. Our data require confirmation in a well-designed prospective clinical trial.

Keywords: breast cancer; cancer; cholangiocarcinoma; integrative medicine; malignant mesothelioma; medicinal mushrooms; personalized medicine; treatment

DOI: https://doi.org/10.3389/fphar.2022.867907

Br J Cancer. 2022 Jul 06.

PFKFB3 works on the FAK-STAT3-SOX2 axis to regulate the stemness in MPM.

Sayantani Sarkar Bhattacharya, Prabhu Thirusangu, Ling Jin, Julie Staub, Viji Shridhar, Julian R Molina.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and often acquires chemoresistance by increasing stemness in tumour tissue, thereby generating cancer stem cells (CSCs). CSCs escape treatment by deploying metabolic pathways to trigger dormancy or proliferation, also gaining the ability to exit and re-enter the cell cycle to hide their cellular identity.
METHODS: We employed various cellular and biochemical assays to identify the role of the glycolytic enzyme PFKFB3, by knocking it down and pharmacologically inhibiting it with PFK158, to determine its anticancer effects in vitro and in vivo by targeting the CSC population in MPM.
RESULTS: Here, we have identified PFKFB3 as a strategic player to target the CSC population in MPM and demonstrated that both pharmacologic (PFK158) and genetic inhibition of PFKFB3 destroy the FAK-Stat3-SOX2 nexus resulting in a decline in conspicuous stem cell markers viz. ALDH, CD133, CD44, SOX2. Inhibition of PFKFB3 accumulates p21 and p27 in the nucleus by decreasing SKP2. Lastly, PFK158 diminishes tumour-initiating cells (TICs) mediated MPM xenograft in vivo.
CONCLUSIONS: This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM.

DOI: https://doi.org/10.1038/s41416-022-01867-7

Front Oncol. 2022 ;12 870352

Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma.

Hely Ollila, Mikko I Mäyränpää, Lassi Paavolainen, Juuso Paajanen, Katja Välimäki, Eva Sutinen, Henrik Wolff, Jari Räsänen, Olli Kallioniemi, Marjukka Myllärniemi, Ilkka Ilonen, Teijo Pellinen.

Background: Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.
Methods: We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.
Results: We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).
Conclusion: High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.

Keywords: dendritic cells; multiplexed fluorescence immunohistochemistry; pleural mesothelioma; prognosis; tumor immune microenvironment

DOI: https://doi.org/10.3389/fonc.2022.870352

Cancers (Basel). 2022 Jun 24. pii: 3108. [Epub ahead of print]14(13):

Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability.

Yurong Song, Shaneen S Baxter, Lisheng Dai, Chelsea Sanders, Sandra Burkett, Ryan N Baugher, Stephanie D Mellott, Todd B Young, Heidi E Lawhorn, Simone Difilippantonio, Baktiar Karim, Yuwaraj Kadariya, Ligia A Pinto, Joseph R Testa, Robert H Shoemaker.

Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/-;Nf2+/- mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting.

Keywords: biomarker; cell line; chromosome instability; genomic instability; immunotherapy; mesothelioma; microsatellite instability; mouse model

DOI: https://doi.org/10.3390/cancers14133108