Roles for Hippo pathway effectors Taz and Yap in cancer and fibrosis
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Abstract
The Hippo pathway is a well-conserved signaling pathway composed of a series of kinases, ending in the LATS1 and LATS2 kinases (LATS1/2), that control the activity of the transcriptional effectors TAZ and YAP (TAZ/YAP). The Hippo pathway is responsive to several external cues, including mechanical stiffness and cell-cell contact. The transcriptional targets of TAZ/YAP have a wide range of effects, including promotion of cell growth, inhibition of apoptosis, regulation of cell fate, and secretion of growth factors. Due to their wide-ranging effects, in these studies we investigated the roles for TAZ and YAP in several disease areas. First, we explored the roles of TAZ/YAP in glutamine addiction, a phenomenon in which cancer cells rely on glutamine for cell growth, in breast cancer. We demonstrated that breast cancer cells with high TAZ/YAP expression exhibit more reliance on glutamine as an energy source than those with low TAZ/YAP. Depletion of TAZ/YAP in high-TAZ/YAP breast cancer cell lines reduced their reliance on glutamine. We showed that TAZ/YAP promote increased transcription of the transaminases GOT1 and PSAT1, which allow for the carbon from glutamine to enter the tricarboxylic acid cycle and generate energy, providing a mechanism by which TAZ/YAP allow for increased processing of glutamine. Second, we explored whether and how loss of Hippo pathway activity contributes to the formation of melanoma. The most common genetic mutation found in melanoma patients is BrafV600E, but this mutation alone is insufficient to drive melanomagenesis, instead promoting an initial proliferative burst that ends in senescence. We found that BrafV600E activates the Hippo pathway to inhibit TAZ/YAP, contributing to the observed growth arrest phenotype in precancerous nevi. We found that deletion of Lats1/2 in melanocytes alone or in combination with BrafV600E expression lead to the rapid development of melanoma in mice. Third, we assessed how TAZ/YAP mediate homeostasis, injury response, and fibrosis in the lung. We explored TAZ/YAP responses in tissue regeneration and fibrosis using the bleomycin injury model in mice. We found that nuclear levels of TAZ/YAP dynamically increase in the epithelium and mesenchyme of the lung after injury; nuclear TAZ/YAP decreases in these populations as the injury resolves. We conditionally deleted Taz and/or Yap in a subset of mesenchymal cells marked by Platelet-Derived Growth Factor Receptor β (PDGFRβ) in adult mice and found that TAZ and YAP play essential roles in lung homeostasis and responses to bleomycin-injury, with TAZ/YAP-deleted animals showing reduced survival. Notable defects included disorganization of lung epithelial and endothelial cells, indicating that TAZ/YAP in PDGFRβ-expressing cells direct signals that coordinate cellular homeostasis in the lung. In total, these studies detail new mechanisms for TAZ/YAP and Hippo signaling in lung homeostasis and injury repair, melanoma development, and metabolic reprogramming in breast cancer.