The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZbinding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation. In CAFs and tumor cells, however, a lack of YAP1 phosphorylation results in its translocation to the nucleus, binding to TEAD transcription factors, and activation of mitogenic pathways. In this review we summarize the literature discussing the central role of YAP1 in CAF activation, the upstream cues that promote YAP1-mediated CAF activation and extracellular matrix remodeling, and how CAFs mediate tumor-stroma crosstalk to support progression, invasion and metastasis in various cancer models. We further highlight YAP1+CAFs functions in modulating an immunosuppressive tumor microenvironment and propose evaluation of several YAP1 targets regarding their role in regulating intra-tumoral immune landscapes. Finally, we propose that co-administration of YAP1- targeted therapies with immune checkpoint inhibitors can improve therapeutic outcomes in patients with advanced tumors.