International Journal of Cancer 2022 March 9 [Link]

Elodie Maille, Jérôme Levallet, Fatéméh Dubois, Martine Antoine, Claire Danel, Christian Creveuil, Julien Mazieres, Jacques Margery, Laurent Greillier, Valérie Gounant, Denis Moro-Sibilot, Olivier Molinier, Hervé Léna, Isabelle Monnet, Emmanuel Bergot, Alexandra Langlais, Franck Morin, Arnaud Sherpereel, Gérard Zalcman, Guénaëlle Levallet

Abstract

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP’s target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H, and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation, and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG post-translational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extra-cell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG post-translational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.