Abstract
YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.
Highlights
Invasion and metastasis are among the hallmarks of cancer [1]
Tumorigenesis is driven by a patient-specific diversity of de-novo mutations, the metastatic process converges on common cellular plasticity mechanisms of normal development hijacked by the cancer cell and driven by interaction with the cancer cells microenvironment
Among them are a large number of receptor tyrosine kinases (RTK)-signaling through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, including insulin-like growth factor 1 receptor (IGF1R); platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR); TGFβ/bone morphogenetic protein (BMP)-signaling through SMAD3/4; NOTCH and its transcriptional effector hairy/enhancer-of-split related 1 (HEY1), WNT and its effector β-catenin and RHO/RAC/ROCK-signaling elicited by a myriad of receptors with tyrosine kinase or serine/threonine kinase activity or from G-protein-coupled receptors or integrins [118]
Summary
Invasion and metastasis are among the hallmarks of cancer [1]. tumorigenesis is driven by a patient-specific diversity of de-novo mutations, the metastatic process converges on common cellular plasticity mechanisms of normal development hijacked by the cancer cell and driven by interaction with the cancer cells microenvironment. It is not surprising that many key molecules of metastatic progression are themselves rarely mutated but activated by intrinsic and extrinsic signaling cues in response to perturbed tissue homeostasis YAP and TAZ act as the ultimate nuclear effectors of signals transmitted from intrinsic biochemical and extrinsic biomechanical cues resulting from changes in the microenvironment and the architecture of tissues, including extracellular matrix rigidity, cell-cell and cell-matrix adhesion, cell density, shape and polarity, all of which play a role in metastatic dissemination and the homing of tumor cells to distant sites. The highly plastic tumor cell shape is repeatedly changing between more round and compact and a more spread-out geometry Cancer cells and their corresponding stroma co-evolve during disease progression, and increasing stiffening of the extracellular matrix assists metastatic spread. TGFβ signaling, to well-studied name only a few well-studied examples
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