Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma

Abstract

Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF, have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease.

Keywords: Hippo pathway; NF2; YAP1/TAZ; malignant mesothelioma.

Figure 1

Schematic representation showing NF2/merlin-Hippo signaling cascade dysregulation in malignant mesothelioma (MM) cells. Signals from the extracellular environment, transduced via cell-cell contact (cadherin), cell-matrix contact (CD44 and integrin), and/or growth factor receptors (receptor tyrosine kinases, RTKs), affect merlin tumor-suppressive activity. Activated (underphosphorylated) merlin regulates the Hippo signaling cascade and suppresses the activity of the YAP1/TAZ transcriptional coactivators. As MMs show frequent alteration of merlin (the NF2 gene product) and Hippo pathway components including LATS1/2, the resultant underphosphorylated (activated) YAP1/TAZ transcriptional coactivators enhance the expression of many pro-oncogenic genes including CCDN1, FOXM1, CTGF, and PLCB4 in MM cells. P: phosphorylation, Ub: ubiquitination.

Figure 2

Signaling cascades and molecules that affect Hippo pathway signaling and YAP1/TAZ activation in MM cells. In addition to cell-to-cell adhesion status and RTK signaling, the Hippo pathway is also regulated by multiple signals including from the GPCR pathway, mevalonate pathway, and energy stress. Upon the activation of other intracellular signaling such as through TGF-β and Wnt signaling pathways, the transcription of YAP1/TAZ-target genes is further enhanced, which induces more aggressive malignant phenotypes of MM cells including cell proliferation, invasion, and EMT.

Figure 3

Overall concept of the current, and “under-clinical-trial” therapies available to patients with malignant mesothelioma (MM), as well as potential novel therapeutic modalities that target the Hippo pathway. Ab, antibody; TKIs, tyrosine kinase inhibitors.