The Hippo Pathway as a Driver of Select Human Cancers

The Hippo pathway plays an important role in organ size control and cell fate, and has been linked to many aspects of tumorigenesis, including cell proliferation, cell differentiation, cell competition, tissue regeneration, cancer metastasis, and cancer therapy resistance. Mutations in Hippo pathway genes are relatively uncommon at a pan-cancer level, but are frequently observed in specific tumor types such as mesothelioma and meningioma. The cancer genes BAP1 and TRAF7 have similar pan-cancer mutation profiles to the Hippo pathway, suggesting potential functional relationships between these genes and the Hippo pathway in the context of cancer. The restricted pan-cancer mutation profile of Hippo pathway genes is possibly explained by tissue- or cell-specific selection pressures that dictate whether such mutations provide an advantage in the context of cell transformation. Two such features are a squamous cell shape and a neuroectodermal developmental origin. The Hippo pathway regulates myriad biological processes in diverse species and is a key cancer signaling network in humans. Although Hippo has been linked to multiple aspects of cancer, its role in this disease is incompletely understood. Large-scale pan-cancer analyses of core Hippo pathway genes reveal that the pathway is mutated at a high frequency only in select human cancers, including malignant mesothelioma and meningioma. Hippo pathway deregulation is also enriched in squamous epithelial cancers. We discuss cancer-related functions of the Hippo pathway and potential explanations for the cancer-restricted mutation profile of core Hippo pathway genes. Greater understanding of Hippo pathway deregulation in cancers will be essential to guide the imminent use of Hippo-targeted therapies. The Hippo pathway regulates myriad biological processes in diverse species and is a key cancer signaling network in humans. Although Hippo has been linked to multiple aspects of cancer, its role in this disease is incompletely understood. Large-scale pan-cancer analyses of core Hippo pathway genes reveal that the pathway is mutated at a high frequency only in select human cancers, including malignant mesothelioma and meningioma. Hippo pathway deregulation is also enriched in squamous epithelial cancers. We discuss cancer-related functions of the Hippo pathway and potential explanations for the cancer-restricted mutation profile of core Hippo pathway genes. Greater understanding of Hippo pathway deregulation in cancers will be essential to guide the imminent use of Hippo-targeted therapies. the ability of cells to alter their phenotype. conditions where Hippo pathway activity is perturbed (genetically or non-genetically) and that cause YAP and TAZ hyperactivation. the core unit of the Hippo pathway that consists of two pairs of kinases (LATS1/2 and MST1/2) and two types of adaptor proteins (SAV1 and MOBKL1A/1B). This cassette is regulated by multiple signals and limits tissue growth by phosphorylating the YAP and TAZ transcriptional coactivator proteins. loss of DNA sequence in both copies of a particular gene. a genetic mutation that results in reduced activity of the encoded protein. a hereditary syndrome caused by inactivating mutations of the NF2 gene, resulting in frequent benign tumors of the nervous system, most prominently bilateral vestibular Schwannomas. a genetic mutation that causes a change in the amino acid sequence of the corresponding protein. a dysfunctional protein whose activity promotes tumor initiation and/or tumor maintenance. an analysis of a diverse range of cancer types. a collection of verified YAP and TAZ target genes whose relative expression can be used as a measure of YAP/TAZ activity.