Conditional expression of a dominant negative-TEAD2 construct modulates YAP1/TEAD-dependent transcription and arrests growth of human malignant mesothelioma MSTO-211H [TEAD2-dn] 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, expression of a dominant negative TEAD2 modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, TEAD2 activity is essential to maintain the growth of mesothelioma tumors in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients. Overall design: Human malignant mesothelioma MSTO-211H cells transfected with a doxycycline-dependent dominant negative-TEAD2 (dn-TEAD2) 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 (dn-TEAD2 expression) on tumor size and gene expression (transcriptome) were evaluated times 0, 24, 96, or 216 hours of treatment.