Potential role of ADAM (A Disintegrin And Metalloprotease) in malignant pleural mesothelioma resistance to chemotherapy

Malignant pleural mesothelioma (MPM) standard therapy is a cisplatin-pemetrexed combination. Unfortunately, MPM cells become very rapidly therapy-resistant in most of cases. Numerous ADAMs (A Disintegrin And Metalloprotease) have been recognized as key contributors to resistance to chemotherapy. The aim of the study was to unveil mechanisms of MPM resistance to treatment and assess the possible implication of ADAM proteases. A measurement of ADAMs expression showed that ADAM8 mRNA is overexpressed as compared to control pleura in human MPM samples and in a mouse model of MPM. In vitro, the mesothelioma cell line AB12 transfected with shRNAs targeting ADAM8 and subsequently exposed to cisplatin displayed a decreased survival as compared to control-ShRNA treated counterparts. Several cisplatin-resistant mesothelioma cell lines were generated by exposing different MPM cell lines to increasing concentrations of cisplatin. A RNA sequencing was performed in order to compare cisplatin-resistant cells to matching parental cells. Surprisingly, a striking overexpression of ADAM8 was observed in cell lines rendered resistant to cisplatin. Moreover, in vivo experiments showed that tumors developed when these cisplatin-resistant cells were injected into the flanks of mice were growing faster and displayed a significant overexpression of ADAM8 mRNA as compared to tumors developed after parental cells injection. In conclusion, our results unveil ADAM8 as a key factor of cisplatin resistance in mesothelioma. Our future researches will focus on the downstream molecular pathways implicating ADAM8 in order to understand how it might affect MPM cisplatin resistance.