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Article

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

by
Silvia Mola
1,2,
Giulia Pinton
1,
Marco Erreni
3,
Marco Corazzari
2,4,5,
Marco De Andrea
2,6,
Ambra A. Grolla
1,
Veronica Martini
2,7,
Laura Moro
1 and
Chiara Porta
1,2,*
1
Department of Pharmaceutical Sciences, Università del Piemonte Orientale “Amedeo Avogadro”, 28100 Novara, Italy
2
Center for Translational Research on Autoimmune & Allergic Diseases (CAAD), Università del Piemonte Orientale “Amedeo Avogadro”, 28100 Novara, Italy
3
Unit of Advanced Optical Microscopy, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
4
Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy
5
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, 28100 Novara, Italy
6
Department of Public Health and Pediatric Sciences, Medical School, University of Turin, 10126 Turin, Italy
7
Department of Translational Medicine (DIMET), University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(9), 4391; https://doi.org/10.3390/ijms22094391
Submission received: 26 March 2021 / Revised: 15 April 2021 / Accepted: 20 April 2021 / Published: 22 April 2021
(This article belongs to the Special Issue Immune Response to Cancer: From Tumor Onset to Therapeutic Approach)
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Abstract

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

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MDPI and ACS Style

Mola, S.; Pinton, G.; Erreni, M.; Corazzari, M.; De Andrea, M.; Grolla, A.A.; Martini, V.; Moro, L.; Porta, C. Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids. Int. J. Mol. Sci. 2021, 22, 4391. https://doi.org/10.3390/ijms22094391

AMA Style

Mola S, Pinton G, Erreni M, Corazzari M, De Andrea M, Grolla AA, Martini V, Moro L, Porta C. Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids. International Journal of Molecular Sciences. 2021; 22(9):4391. https://doi.org/10.3390/ijms22094391

Chicago/Turabian Style

Mola, Silvia, Giulia Pinton, Marco Erreni, Marco Corazzari, Marco De Andrea, Ambra A. Grolla, Veronica Martini, Laura Moro, and Chiara Porta. 2021. "Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids" International Journal of Molecular Sciences 22, no. 9: 4391. https://doi.org/10.3390/ijms22094391

APA Style

Mola, S., Pinton, G., Erreni, M., Corazzari, M., De Andrea, M., Grolla, A. A., Martini, V., Moro, L., & Porta, C. (2021). Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids. International Journal of Molecular Sciences, 22(9), 4391. https://doi.org/10.3390/ijms22094391

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