bims-mesote 2022-08-07 papers

Issue of 2022–08–07
six papers selected by
Laura Mannarino, Humanitas Research

J Thorac Oncol. 2022 Aug;pii: S1556-0864(22)00241-6. [Epub ahead of print]17(8): e67-e69

Revisiting "BAP1ness" in Malignant Pleural Mesothelioma.

DOI: https://doi.org/10.1016/j.jtho.2022.04.014

Life Sci. 2022 Jul 29. pii: S0024-3205(22)00543-4. [Epub ahead of print]306 120843

Repurposing clofazimine for malignant pleural mesothelioma treatment - In-vitro assessment of efficacy and mechanism of action.

Vineela Parvathaneni, Rameswari Chilamakuri, Nishant S Kulkarni, Xuechun Wang, Saurabh Agarwal, Vivek Gupta.

AIMS: Malignant pleural mesothelioma (MPM) is a rare cancer of lungs' pleural cavity, with minimally effective therapies available. Thus, there exists a necessity for drug repurposing which is an attractive strategy for drug development in MPM. Repurposing of an old FDA-approved anti-leprotic drug, Clofazimine (CFZ), presents an outstanding opportunity to explore its efficacy in treating MPM.
MAIN METHODS: Cytotoxicity, scratch assay, and clonogenic assays were employed to determine CFZ's ability to inhibit cell viability, cell migration, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of CFZ in MSTO-211H cell line. Gene expression analysis was performed using RT-qPCR assays to determine the CFZ's effect of key genes. Western blot studies were performed to determine CFZ's ability to induce apoptosis its effect to induce autophagy marker.
KEY FINDINGS: CFZ showed significant cytotoxicity against both immortalized and primary patient-derived cell lines with IC50 values ranging from 3.4 μM (MSTO-211H) to 7.1 μM (HAY). CFZ significantly impaired MPM cell cloning efficiency, migration, and tumor spheroid formation. 3D Spheroid model showed that CFZ resulted in reduction in spheroid volume. RT-qPCR data showed downregulation of genes β-catenin, BCL-9, and PRDX1; and upregulation of apoptosis markers such as PARP, Cleaved caspase 3, and AXIN2. Additionally, immunoblot analysis showed that CFZ down-regulates the expression of β-catenin (apoptosis induction) and up-regulates p62, LC3B protein II (autophagy inhibition).
SIGNIFICANCE: It can be concluded that CFZ could be a promising molecule to repurpose for MPM treatment which needs numerous efforts from further studies.

Keywords: 3D spheroid; Apoptosis; Asbestos; Autophagy; Clofazimine; Drug repurposing; Malignant pleural mesothelioma; Mesothelioma

DOI: https://doi.org/10.1016/j.lfs.2022.120843

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2022 Jul 20. 40(7): 487-494

[Expression and clinical significance of COL1A1 and COL1A2 genes in malignant pleural mesothelioma tissues].

B Li, Y Q Pu, Z L Li, Y Zhao, J J Zi, W Xiong.

Objective: To investigate the expression levels and clinical significance of collagen typeⅠ α1 chain (COL1A1) and collagen type Ⅰ α2 chain (COL1A2) in malignant pleural mesothelioma (MPM) tissues. Methods: In January 2020, MPM tissues and adjacent normal pleural tissues were collected from 26 MPM patients, and the expression levels of COL1A1 and COL1A2 genes in the tissues were determined by quantitative reverse transcription PCR, and the efficacy of both levels in diagnosing MPM was assessed using receiver operating characteristic (ROC) curves. The relationship between COL1A1 and COL1A2 gene expression and clinicopathological features was analyzed by the Cancer Genome Atlas (TCGA) database, and the relationship between the expression levels of both and overall survival (OS) and disease-free progression survival (DFS) of MPM patients was dynamically analyzed by gene expression profiling, and the factors affecting the prognosis of MPM patients were explored by Cox proportional risk regression model. The TIMER 2.0 platform was used to explore the relationship between COL1A1 and COL1A2 gene expression in MPM and tumor immune infiltrative cells. Results: Compared with normal pleural tissues, the expression of COL1A1 and COL1A2 genes was significantly increased in MPM tissues (P<0.01) , and their expression was positively correlated (P<0.001) . The ROC curves showed that the area under the curve for COL1A1 and COL1A2 expression levels diagnostic of MPM was 0.900 and 0.897, respectively. The expression of COL1A1 gene was correlated with tumor type in MPM patients (P<0.05) , and COL1A2 gene expression was correlated with T stage in MPM patients (P<0.05) . Both COL1A1 and COL1A2 gene expression were associated with OS in MPM patients (Logrank P<0.05) , but there was no significant correlation with DFS (Logrank P>0.05) . Cox multivariate analysis showed that patients with high COL1A1 and COL1A2 gene expression and biphasic mixed MPM had a higher risk of death (P<0.05) . TIMER 2.0 platform analysis showed that COL1A1 and COL1A2 gene expression in MPM patients was positively correlated with macrophages, COL1A2 gene expression in MPM was negatively correlated with neutrophils (P<0.05) . Conclusion: High expression of COL1A1 and COL1A2 genes in MPM tissues is valuable for diagnosis, disease prediction and prognostic assessment of MPM, and both may jointly contribute to the development of MPM.

Keywords: Clinical significance; Collagen type Ⅰ alpha 1 chain; Collagen typeⅠalpha 2 chain; Malignant pleural mesothelioma; Mesothelioma; The Cancer Genome Atlas (TCGA) database

DOI: https://doi.org/10.3760/cma.j.cn121094-20210621-00298

NAR Cancer. 2022 Sep;4(3): zcac024

KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM).

Eugenia Lorenzini, Federica Torricelli, Raffaella Zamponi, Benedetta Donati, Veronica Manicardi, Elisabetta Sauta, Italo Faria do Valle, Francesca Reggiani, Mila Gugnoni, Gloria Manzotti, Valentina Fragliasso, Emanuele Vitale, Simonetta Piana, Valentina Sancisi, Alessia Ciarrocchi.

Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, which incidence is increasing in many countries. MPM escapes the classical genetic model of cancer evolution, lacking a distinctive genetic fingerprint. Omics profiling revealed extensive heterogeneity failing to identify major vulnerabilities and restraining development of MPM-oriented therapies. Here, we performed a multilayered analysis based on a functional genome-wide CRISPR/Cas9 screening integrated with patients molecular and clinical data, to identify new non-genetic vulnerabilities of MPM. We identified a core of 18 functionally-related genes as essential for MPM cells. The chromatin reader KAP1 emerged as a dependency of MPM. We showed that KAP1 supports cell growth by orchestrating the expression of a G2/M-specific program, ensuring mitosis correct execution. Targeting KAP1 transcriptional function, by using CDK9 inhibitors resulted in a dramatic loss of MPM cells viability and shutdown of the KAP1-mediated program. Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.

DOI: https://doi.org/10.1093/narcan/zcac024

J Thorac Oncol. 2022 Aug;pii: S1556-0864(22)00298-2. [Epub ahead of print]17(8): 949-952

Does the Amount of Asbestos Exposure Influence Prognosis?

Haining Yang, Giovanni Gaudino, Fabrizio Bardelli, Michele Carbone.

DOI: https://doi.org/10.1016/j.jtho.2022.06.003

J Thorac Oncol. 2022 Aug;pii: S1556-0864(22)00272-6. [Epub ahead of print]17(8): e69-e70

Response to "Revisiting 'BAP1ness' in Malignant Pleural Mesothelioma".

BAP1 Study Group

DOI: https://doi.org/10.1016/j.jtho.2022.05.013