YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer

Abstract

Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed-forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial⁻mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-β signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer.

Keywords: Hippo pathway; TAZ; TGF-β; Wnt; YAP; cancer; fibrosis; mechanotransduction.

Figure 1

The activation of Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) in epithelial cells and fibroblasts. In epithelial cells, the disruption of cell polarity, loss of cell contact, and increased cell stress signals activate YAP/TAZ, which promotes cell proliferation and the epithelial–mesenchymal transition (EMT), and inhibits apoptosis. In contrast, in fibroblasts, YAP/TAZ act as sensors of extracellular matrix (ECM) stiffness through the mechanotransduction pathway. YAP/TAZ also stimulate the production of fibrogenic factors and ECM proteins and enhance cell contraction. This process promotes tissue stiffness, thus forming a feed-forward loop of fibroblast activation and tissue fibrosis. YAP/TAZ can also be activated in epithelial cells of fibrotic tissues due to increased ECM stiffness.

Figure 2

The function of YAP/TAZ in cancer cells and in the cancer microenvironment. YAP/TAZ enhance the proliferation, survival, metastasis, and drug resistance of cancer cells. The cancer microenvironment comprises ECM and stromal cells, such as cancer-associated fibroblasts (CAFs) and immune cells. The activation of YAP/TAZ in CAFs promotes migration and invasion of cancer cells, and angiogenesis. YAP/TAZ facilitate tumor immune evasion by suppressing cytotoxic T cells through PD-L1 expression in cancer cells, and supporting myeloid-derived suppressor cells (MDSCs) and regulatory T cells.