Different pathway disregulations correlate with distinct pleural mesothelioma histotypes

The mechanism leading to the onset of pleural mesothelioma (PM), a fatal cancer linked to asbestos exposure, remains largely elusive due to multiple genetic mutations and pathways dysregulations. There are three main PM subtypes, epithelioid, biphasic, and sarcomatoid, characterized by different survival rate, 19, 12 and 4 months, respectively. Significant dysregulation of epithelial-mesenchymal transition (EMT) and signaling pathways, such as Hippo and Wnt/β-catenin have been reported in PM. This study aimed to elucidate molecular mechanisms underlying different PM histotypes through the analysis of genes involved in key cell transformation pathways, in order to simplify the classification of PM into two only histotypes, epithelioid and non-epithelioid, as recently proposed. To this end, gene expression was investigated in PM cell lines by droplet digital PCR (ddPCR). PM cells were from epithelioid (IST-Mes2, MPP89), biphasic (MSTO-211H), and sarcomatoid (PPM-Mill) histotypes. Our molecular investigation revealed different expression patterns of EMT-related genes, with epithelioid cell lines showing higher E-cadherin, N-cadherin, and fibronectin 1, and lower Vimentin gene expressions compared to non-epithelioid PM. Additionally, in epithelioid cell lines the Hippo pathway tested dysregulated, with a high YAP gene expression. Western blot analyses were in agreement with most of the ddPCR data, with discrepancies in β-catenin and TAZ gene expressions. These findings indicate a complex interplay of different molecular pathways in PM, which are linked to distinct histotypes and cancer cell proliferation. In conclusion, new pathways dysregulations tested herein may account for specific cellular and molecular characteristics of PM contributing to a better characterization of epithelioid and nonepithelioid histotypes.