Abstract
The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.
Highlights
Overview of Pediatric Sarcomas Sarcomas account for ~1% of all malignancies, but occur with higher frequency in children compared to adults, comprising ~15% of all childhood malignancies [1]
While this study suggests a role for MST1 in myogenic differentiation, connections between MST1 activation by caspase 3 and the canonical Hippo pathway in muscle remain to be determined
YAP1 expression is elevated and correlates with tumor staging and an increase in Hippo target genes Suppression of yes-associated protein 1 (YAP) promotes differentiation, and decreases cell proliferation and tumor growth YAP is a direct target of SRY-box 2 (SOX2) in osteoprogenitors and YAP1 expression is altered by SOX2 abundance OS transgenic mice with upregulated Hedgehog signaling display high YAP1 expression The long non-coding RNA H19 is aberrantly induced by YAP1 overexpression
Summary
Overview of Pediatric Sarcomas Sarcomas account for ~1% of all malignancies, but occur with higher frequency in children compared to adults, comprising ~15% of all childhood malignancies [1]. In another study using murine cardiac muscle, knockdown of Hippo components Sav, Mst1/2, or Lats results in increased Yap activity and cardiomyocyte proliferation with phenotypic cardiomegaly Gene profiling from these mice reveal an elevated WNT signature, and the phenotypic effects could be offset by conditional loss of one β-catenin allele [59]. The differentiated phenotype of OS cells induced by Nf2 could be overcome by either overexpressing wild-type or constitutively active mutant Yap, but not mutant Yap with a deficient TEAD-binding site This regulation of Yap by Sox occurs through canonical Hippo signaling, as suppression of either Mst1/2 or Lats1/2 abolished Nf2-induced osteogenic differentiation as well as changes in Yap expression and function [97]. The molecular basis for dysregulated Hippo signaling in EWS is beginning to be studied, as summarized below
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