Conditional expression of sh-YAP1 modulates YAP1/TEAD-dependent transcription and causes regression of established human malignant mesothelioma MSTO-211H [sh-YAP1] xenografts.

We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients. Overall design: Malignant pleural mesothelioma MSTO-211H cells transfected with a doxycycline-dependent sh-YAP1 construct were inoculated subcutaneously in mice and allowed to grow to about 300 mm3 under glucose supplementation. At time 0, the mice were split into groups receiving doxycycline or not. The effects of doxycycline supplementation (sh-YAP1 expression) on tumor size and gene expression (transcriptome) were evaluated at times 0 (before treatment), 24, 96, or 216 hours of treatment.