YAP1 is essential for malignant mesothelioma tumor maintenance

Abstract

Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.

Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways

“…SLC39A1 encodes a zinc transporter and is a known tumor suppressor gene controlled by YAP, part of the Hippo pathway 34 . The Hippo pathway is known to be dysregulated in mesothelioma and therefore loss of this gene is potentially a driver of mesothelioma 35 . Because the two fusion events breakpoints in SLC39A1 are slightly different, and the two fusion events involve breakpoints in different members of the ATP1A family, two distinct inversions on both homologous chromosomes is possible.…”

“…34 The Hippo pathway is known to be dysregulated in mesothelioma and therefore loss of this gene is potentially a driver of mesothelioma. 35 Because the two fusion events breakpoints in SLC39A1 are slightly different, and the two fusion events involve breakpoints in different members of the ATP1A family, two distinct inversions on both homologous chromosomes is possible. However, one event involving a single inversion followed by a deletion on one chromosome, is more likely (Figure 3).…”

YAP/TEAD-induced PRIM1 contributes to the progression and poor prognosis of gastric carcinoma

“…After Hippo signaling is inhibited, YAP1 accumulates in the nucleus and interacts with TEAD transcription factors. The activation of the YAP1/TEAD transcriptional regulatory complex induces malignant cancer behaviors, such as promoting cell proliferation and inhibiting cell apoptosis, in a variety of cancers [44] , [45] , [46] . Further research showed that TEAD directly bound to the promoter region of PRIM1, indicating that PRIM1 was a downstream target of the YAP1/TEAD transcriptional regulatory complex.…”

Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways

“…The Hippo pathway is known to be dysregulated in mesothelioma and therefore loss of this gene is potentially a driver of mesothelioma [35]. Because the two fusion events breakpoints in SLC39A1 are slightly different, and the two fusion events involve breakpoints in different members of the ATP1A family, two distinct inversions on both homologous chromosomes is possible.…”