LAUSR

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer that lacks effective therapeutic options, owing to chemotherapeutic resistance and lack of currently targetable oncogenic mutations. However, mutations in histone modifiers documented in MPM represent exciting potential therapeutic targets. Wirawan and colleagues used estrogen receptor sensitive Snail variant mesenchymal and sarcomatoid-like MPM cell lines to show that lysine-specific demethylase 1 (LSD1) drives a MPM mesenchymal phenotype, tumor cell migration, and cisplatin resistance. The authors integrated microarray, phosphokinase array, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses to identify milk fat globulin protein E8 (MFGE8) as the LSD1-mediated driver of cisplatin resistance. Subsequent experiments demonstrated that MFGE8 interaction with integrin b3 drives FAK and AKT phosphorylation, initiating a positive feedback loop that upregulates Snail expression and promotes its associatedmesenchymal phenotype. In sum, the work presented suggests that LSD1 may be a multifactorial therapeutic target for MPM.