A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas

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.

Keywords: Ewing sarcoma; Hippo; mesenchymal; osteosarcoma; pediatric cancers; rhabdomyosarcoma; sarcoma; targeted therapy.

Figure 1

Schematic representation of the mammalian Hippo signaling cascade. Canonical Hippo transduction involves MST1/2 and LATS1/2 kinases, which, in conjunction with SAV1 and MOB1, phosphorylate, and inhibit the transcriptional co-activators YAP and TAZ. Regulation of YAP and TAZ are governed by plasma membrane proteins, cytoskeletal adaptor proteins, regulatory cross-talk from other signaling pathways, and intrinsic and extrinsic mechanical cues with the actin cytoskeleton. For simplicity, not all the known protein–protein interactions and regulators of Hippo signaling are represented. When Hippo signaling is “OFF”, YAP/TAZ translocate to the nucleus to serve as transcriptional co-activators for TEADs as well as other transcription factors (only a few of which are represented here) involved in cellular proliferation, differentiation, self-renewal, and apoptosis. See text for additional details.

Figure 2

Mechanical and physical influences on MSC cell fate. Cell geometry and ECM stiffness regulate MSC lineage commitment into neurons, adipocytes, skeletal muscle cells, or osteoblasts. (A) Increasing ECM stiffness in vitro (by increasing type I collagen concentration and crosslinking) compromises tissue organization, inhibits apoptosis and lumen formation, and destabilizes adherens junctions. Through modeling different ECM elasticities in vitro, MSCs differentiate into the varying lineages at elasticities that recapitulate the physiological ECM stiffness of their corresponding natural niche (shown as colored lines, with peaks indicating maximal differentiation). Pa, Pascal. (B) When MSCs are either cultured on a soft matrix or are manipulated into a small round shape, YAP/TAZ remain inhibited in the cytoplasm and MSCs differentiate into adipocytes. However, when MSCs are either grown on a stiff matrix or stretched and manipulated into a “spread-out” morphology, YAP/TAZ localize to the nucleus as MSCs differentiate into osteoblasts. (C) Corresponding histologic sarcoma subtype [2013 WHO classification (230)], which may reflect varying lineage differentiation from mesenchymal progenitor cells. This represents only a theoretical link between mechanotransduction influencing mesenchymal progenitors and sarcoma, and not all sarcoma subtypes are represented. Figures (A,B) are modified with permission from Halder et al. (108) and Piccolo et al. (117).

Figure 3

Pharmacologic modulators of the Hippo pathway. The Hippo cascade involves many protein–protein interactions that could serve as novel targets, and numerous pharmacologic compounds either directly or indirectly modulate Hippo activity. Some of the compounds activate Hippo components and others have an inhibitory role. While not all referenced studies have proven that modulation of upstream regulators result in concomitant changes in YAP or TAZ activity, these provide proof of principal that targeting Hippo signaling could be harnessed as a novel strategy to treat sarcomas. This is not an inclusive list, and other compounds are known to modulate Hippo components. Figure is modified with permission from Park et al. (202). Letters in Red correspond to the letters in the Key in Table 3.