bims-mesote 2021-05-02 papers

Issue of 2021‒05‒02
three papers selected by
Laura Mannarino
Humanitas Research

Cancers (Basel). 2021 Apr 07. pii: 1761. [Epub ahead of print]13(8):

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity.

Luka Brcic, Alexander Mathilakathu, Robert F H Walter, Michael Wessolly, Elena Mairinger, Hendrik Beckert, Daniel Kreidt, Julia Steinborn, Thomas Hager, Daniel C Christoph, Jens Kollmeier, Thomas Mairinger, Jeremias Wohlschlaeger, Kurt Werner Schmid, Sabrina Borchert, Fabian D Mairinger.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell-cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma.

Keywords: epithelioid; gene expression; immunogenicity; pleural mesothelioma; sarcomatoid

DOI: https://doi.org/10.3390/cancers13081761

Int J Mol Sci. 2021 Apr 22. pii: 4391. [Epub ahead of print]22(9):

Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids.

Silvia Mola, Giulia Pinton, Marco Erreni, Marco Corazzari, Marco De Andrea, Ambra A Grolla, Veronica Martini, Laura Moro, Chiara Porta.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes' recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.

Keywords: EPZ-6438; EZH2; epigenetic reprogramming; malignant pleural mesothelioma; monocytes; spheroids; tazemetostat; tumor microenvironment; tumor-associated macrophages

DOI: https://doi.org/10.3390/ijms22094391

Cancers (Basel). 2021 Apr 01. pii: 1660. [Epub ahead of print]13(7):

Malignant Pleural Mesothelioma Interactome with 364 Novel Protein-Protein Interactions.

Kalyani B Karunakaran, Naveena Yanamala, Gregory Boyce, Michael J Becich, Madhavi K Ganapathiraju.

Malignant pleural mesothelioma (MPM) is an aggressive cancer affecting the outer lining of the lung, with a median survival of less than one year. We constructed an 'MPM interactome' with over 300 computationally predicted protein-protein interactions (PPIs) and over 2400 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from Biological General Repository for Interaction Datasets (BioGRID) and Human Protein Reference Database (HPRD). Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, and gene expression in microarray experiments, and classifies the pairwise features as interacting or non-interacting based on a random forest model. We validated five novel predicted PPIs experimentally. The interactome is significantly enriched with genes differentially ex-pressed in MPM tumors compared with normal pleura and with other thoracic tumors, genes whose high expression has been correlated with unfavorable prognosis in lung cancer, genes differentially expressed on crocidolite exposure, and exosome-derived proteins identified from malignant mesothelioma cell lines. 28 of the interactors of MPM proteins are targets of 147 U.S. Food and Drug Administration (FDA)-approved drugs. By comparing disease-associated versus drug-induced differential expression profiles, we identified five potentially repurposable drugs, namely cabazitaxel, primaquine, pyrimethamine, trimethoprim and gliclazide. Preclinical studies may be con-ducted in vitro to validate these computational results. Interactome analysis of disease-associated genes is a powerful approach with high translational impact. It shows how MPM-associated genes identified by various high throughput studies are functionally linked, leading to clinically translatable results such as repurposed drugs. The PPIs are made available on a webserver with interactive user interface, visualization and advanced search capabilities.

Keywords: drug repurposing; malignant mesothelioma; network analysis; protein-protein interactions; systems biology

DOI: https://doi.org/10.3390/cancers13071660