Genetic alterations and deregulation of hippo pathway as a pathogenetic mechanism in bone and soft tissue sarcoma

Citation: Salguero-Aranda, C.; Olmedo-Pelayo, J.; de Álava, E.; Amaral, A.T.; Díaz-Martín, J. Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma. Cancers 2022,14, 6211. https://doi.org/10.3390/ cancers14246211 Academic Editor: Joachim Kremerskothen Received: 18 November 2022 Accepted: 13 December 2022 Published: 15 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Review Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma Carmen Salguero-Aranda 1,2,3,† , Joaquín Olmedo-Pelayo 1,2,3,†, Enrique de Álava 1,2,3,* , Ana Teresa Amaral 1,2,3,‡ and Juan Díaz-Martín1,2,3,*,‡ 1Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla, 41013 Seville, Spain 2Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III (CB16/12/00361, CIBERONC-ISCIII), 28029 Madrid, Spain 3Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain *Correspondence: [email protected] (E.d.Á.); [email protected] (J.D.-M.) † These authors contributed equally to this work as first authors. ‡ These authors contributed equally to this work as senior authors. Simple Summary: Cancer is a genetic disease that is caused by changes in genes controlling cell growth, migration, and differentiation. Usually, cancer cells hijack processes used by healthy cells during organism development. The Hippo pathway is a developmental signaling system with a critical role in tissue and organ size regulation, which is frequently deregulated in cancer. Indeed, the contribution of Hippo dysfunction to cancer development has been extensively reported in carcinomas, but it is increasingly recognized in sarcomas. Sarcomas are rare cancers that develop in the bones and soft tissues, encompassing a large variety of different subtypes. Here we review the relevance of the Hippo pathway in specific sarcoma subtypes, with a focus on both the genetic alterations in Hippo pathway genes as well as other molecular mechanisms involved in its deregulation. Abstract: The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm. Keywords: Hippo pathway; YAP; TAZ; sarcoma; gene fusion 1. Introduction The Hippo pathway is an evolutionary and functionally conserved pathway that controls developmental processes, differentiation, and regeneration by regulating organ size and tissue homeostasis [ 1 , 2 ]. This pathway was initially discovered in Drosophila melanogaster due to tumor suppressor screens and was later revealed to be conserved Cancers 2022,14, 6211. https://doi.org/10.3390/cancers14246211 https://www.mdpi.com/journal/cancers Cancers 2022,14, 6211 2 of 30 in mammals. These studies identified Warts (Wts,LATS1/2 in humans) [ 3 , 4 ] and Hippo (Hpo, or STK4/3 encoding MST1/2 in humans) [ 5 , 6 ] genes, which encode the kinases that constitute the principal phosphorylation cascade to the signaling pathway. Likewise, in flies, Hippo mutants display phenotypes of extremely sized organs and apparently resemble a hippopotamus, naming this signaling pathway as it is currently known—the Hippo pathway [5]. In recent years, aberrations on the Hippo pathway have been increasingly associated with cancer development. Thus, many studies have experimentally established its tumor suppressor function. For example, Mst1/2 loss leads to uncontrolled cell proliferation and differentiation in a mouse liver [ 7 ], and Yap1/Taz overexpression, the transcriptional coactivators of the pathway, triggers tissue overgrowth and cancer [ 8 , 9 ]. Therefore, dysregulation of the hippo pathway has been reported in various cancer types, including sarcomas [ 7 , 10 – 16 ], and correlated with poor prognosis [ 17 ]. This review will focus on the genomic alterations disturbing the Hippo pathway and how these aberrations might be potential therapeutic targets in bone and soft tissue sarcomas. 2. The Hippo Signaling Pathway: Critical Components in Mammals and Basic Biology The primary function of the Hippo pathway is to inhibit proliferation and promote apoptosis, thereby controlling organ growth [ 18 ]. This role is arbitrated by a cascade of kinases that transmit, from the plasma to the nucleus, various upstream mechanical, architectural, and metabolic signals. The Hippo regulating plasma membrane proteins principally include E-cadherin (CHD1) [ 19 ], protocadherin FAT4 [ 20 ], wingless-related integration (WNT) [ 21 – 23 ], the Crumbs polarity complex [ 24 ], LIM domain-containing protein Ajuba (AJUBA) [ 25 ], the hyaluronic acid receptor CD44 [ 26 ], and G-protein coupled receptors (GPCR) [ 27 ]. These proteins control the members of the upstream intracellular pathway, which include neurofibromatosis type 2 (NF2), also known as merlin [ 28 ], kidney and brain protein (KIBRA or WWC1) [ 29 ], Ras-association domain family members (RASSF1–10) [ 30 ], TAO kinases (1–3) [ 31 ] and angiomotin (AMOT) [ 32 ]. All these upstream regulators play a vital role in initiating the cascade of phosphorylation of the core Hippo pathway members. When the Hippo pathway is activated, the STE20-like kinase 1/2 (MST1/2) is phosphorylated on threonine 183/180, mainly by TAO kinases [ 33 ], although it has been described that the activation can be achieved by MST1/2 autophosphorylation itself [ 34 ]. Active MST1/2 then phosphorylates the large tumor suppressor kinase 1/2 (LATS1/2) protein [ 35 ], but LATS1/2 can also be directly activated by the upstream regulators NF2, AJUBA, and TAO kinases [ 28 , 36 , 37 ]. MST1/2 also phosphorylates the Salvador family WW domaincontaining protein 1 (SAV1) and MOB kinase activator 1A and 1B (MOB1A/B), which are scaffold proteins that coordinate the phosphorylation of MST1/2 and LATS1/2 protein kinases [ 38 , 39 ]. In turn, active LATS1/2 phosphorylates the paralogous transcriptional cofactors Yes-associated protein 1 (YAP) (gene symbol, YAP1) and PDZ-binding motif (TAZ) (gene symbol, WWTR1) on the serine S127 and S89, respectively, which results in their inactivation through translocation from the nucleus to the cytosol, binding with 14-3-3 protein and proteasomal degradation [ 40 , 41 ]. Thus, the cofactors TAZ and YAP are negatively regulated by the Hippo pathway. When the Hippo signaling pathway is inactivated, non-phosphorylated YAP or TAZ are stabilized and translocated into the nucleus. Because of the lack of DNA-binding domains of YAP/TAZ, they require to cooperate with DNA-binding transcription factors to induce the expression of genes involved in cell proliferation, migration, survival, tissue growth, and inhibition of apoptosis [ 42 ]. YAP and TAZ interact preferentially with transcriptional enhanced associate domain (TEAD) proteins (TEAD1–4) [ 43 , 44 ] but also with other transcription factors such as SMAD family members [ 45 , 46 ], Erb-B2 receptor tyrosine kinase 4 (ERBB4) [ 47 ], T-box transcription factor 5 (TBX5) [ 48 , 49 ], RUNX family transcription factor 1, 2 and 3 (RUNX1/2/3) [ 50 , 51 ], early-growth response 1 (EGR1) [ 52 ], hypoxia-inducible factor 1 alpha (HIF1A α ) [ 53 ], core-binding factor subunit beta (CBFB) Cancers 2022,14, 6211 3 of 30 (also called PEBP2) [ 54 ] and tumor protein p73 [ 55 ]. Depending on the binding of YAP to one of these DNA-binding transcription factors and, subsequently, associated promoters, diverse target genes are activated. For example, target genes of the YAP/TAZ-TEAD complex include CYR61,CTGF,AREG, or MYC; YAP-TBX5 complex induces the expression of transcriptional targets such as BCL2L1 and BIRC5; and YAP-ERBB4 regulates the expression of CTGF,CYR61, and ANKRD1 [ 42 ], involved in cell proliferation, growth, migration, and survival. In addition to the central inhibitory kinase core, the regulation of YAP and TAZ activity is also controlled by multiple Hippo-independent mechanisms. There is extensive crosstalk with other pathways that influence YAP/TAZ activity beyond the canonical Hippo pathway, such as WNT signaling, TGF β signaling, GPCR, Rho GTPases or tyrosine kinases-PI3K-AKT signaling [ 56 , 57 ]. Of note, the prominent role of YAP and TAZ integrating morphogenic signals in mechanotransduction processes is modulated both by Hippo-dependent and independent mechanisms. The organization of the actin cytoskeleton seems to be the main input of mechanical cues involving Rho-family GTPases and ROCK (Rho-associated protein kinase) proteins that control F-actine polymerization and ultimately affect YAP/TAZ activity in a LATS-dependent or independent manner [ 57 , 58 ]. Moreover, cell-substratum interaction mediated by integrins promotes the activation of YAP/TAZ by SRC kinase. Indeed, SRC and other SRC family kinases can activate YAP/TAZ through multiple mechanisms, including direct phosphorylation conferring protein stability, enhancing transcriptional activity, and/or interaction with other transcription factors. SRC-mediated activation of YAP/TAZ can also occur through repression of LATS or Hippo pathway-independent mechanisms [59,60]. 3. Deregulation of the Hippo Signaling Pathway in Bone and Soft Tissue Sarcoma Given the critical role of the Hippo pathway in regulating these multiple cellular processes, it is not surprising that aberrant activation of YAP/TAZ leads to uncontrolled cell proliferation and malignant transformation. Indeed, cancer cells commonly hijack the Hippo pathway to acquire malignant properties. There is extensive evidence that increased expression of YAP/TAZ associates with tumor onset and progression in a large variety of cancers [ 17 ]. Actually, the Cancer Genome Atlas (TCGA) project that performed multi-omics profiling in a pan-cancer cohort of 9125 patients across 33 cancer types and characterization of 19 Hippo core genes indicated widespread deregulation of the Hippo pathway members in human cancers. Their main finding is that Hippo signaling is especially relevant in the pathogenesis of carcinomas with squamous cell differentiation. This was mainly attributed to the elevated proportion of cases with YAP1/WWTR1 genomic amplification and high expression heterogeneity of YAP/TAZ target gene signature, which correlated with decreased overall survival of patients with squamous cell cancers. With regard to sarcomas, attending to this report, they seem to be among the malignancies with less genomic alterations in Hippo-related genes and exhibited a poor correlation between YAP/TAZ target gene signature and overall survival. The somatic copy number alteration study showed a significant deletion peak in 17p in sarcomas, where TAOK1 resides [ 16 ]. However, it is important to bear in mind that the data analyzed corresponded to a small subset of sarcoma subtypes (leiomyosarcomas, dedifferentiated liposarcomas, and myxofibrosarcomas/undifferentiated pleomorphic sarcomas), which does not represent the enormous diversity of different entities. Besides, pooled analysis of different sarcoma entities may hinder specific features. Therefore, the functional relevance of Hippo signaling in different types of sarcomas should be evaluated in specific entities. Sarcomas are a highly heterogeneous and complex group of mesenchymal malignancies, both in terms of morphology and pathobiology, that represent <1% of all malignant neoplasms in adults [ 61 ].The WHO classification of bone and soft tissue sarcoma listed approximately 100 different sarcomas and mesenchymal tumors of intermediate malignancy. From the genomic point of view, sarcomas can be broadly classified into two groups. Around 1/3 are translocation-associated sarcomas (t-sarcomas), mainly arising in children Cancers 2022,14, 6211 4 of 30 and young adults, and 2/3 are non-t sarcomas that display complex karyotypes with no specific genomic patterns. In the case of t-sarcomas, the translocation generates a specific fusion gene, which is the driver oncogene of the disease and is an important hallmark to differentiate between different neoplasms among the large variety of entities. In fact, t-sarcomas show an overall low mutational burden apart from gene fusion. Interestingly, several t-sarcomas exhibit recurrent translocations involving Hippo-related genes. Particularly, the genes YAP1 and WWTR1 are identified to be rearranged in certain subtypes of sarcomas and in other unrelated tumor types, such as supratentorial ependymoma (YAP1::MAMLD1, YAP1::FAM118B), cervical squamous cell carcinoma and endocervical adenocarcinoma (YAP1::SS18), poroma/porocarcinoma (YAP1::MAML2,YAP1::NUTM1), or NF2-wild type meningioma (YAP1::MAML2,YAP1::FAM118B,YAP1::PYGO1,YAP1::LMO1) [ 62 ]. Moreover, Hippo pathway deregulation mediates the oncogenic properties of other recurrent sarcoma gene fusions. Intriguingly, most of the reports describing the functional relevance of the Hippo pathway in sarcomas deal with t-sarcomas, despite the fact that they represent only 1/3 of the mesenchymal malignancies. Several studies have demonstrated that the Hippo pathway is deregulated in sarcomas. For example, fusion genes involving WWTR1 and YAP1 are found in nearly all cases of epithelioid haemangioendothelioma [ 63 , 64 ]; YAP1 copy number gain has been described in embryonal rhabdomyosarcoma [ 65 ] and frequent hypermethylation of MST1,MST2 and RASSF1A has been shown in several subtypes of soft tissue sarcoma [ 66 ]. Furthermore, a study encompassing an immunohistochemistry (IHQ) assessment of TAZ and YAP in 159 sarcomas representing the most prevalent types showed that 50% and 66% of samples exhibit activation (or nuclear location) of YAP and TAZ, respectively [ 67 ]. A later study analyzed the expression levels of YAP and TAZ by IHQ in a cohort of 486 sarcoma tissues. Nuclear YAP and TAZ expression levels were detected in 53% and 33% to be moderate to intense, respectively [ 68 ]. Additionally, deregulation of the hippo pathway has been related to poor prognosis in several subtypes of sarcomas [ 67 , 69 – 71 ]. These pieces of evidence suggest that the Hippo pathway plays a crucial role in sarcoma tumorigenesis, progression, and outcome. In this section, we will discuss alterations that affect Hippo pathway members in specific subtypes of sarcomas (Figure 1and Table 1). Table 1. Deregulation mechanisms of Hippo pathway in sarcomas. Sarcoma Subtype T-Sarcoma/ Non T-Sarcoma Hippo Member Deregulation Mechanism Deregulating Factors or Genetic Aberration References OS Non T-Sarcoma YAP Transcriptional H19 lncRNA/ Hedgehog signalling [72] SOX2 [73] Post-transcriptional B4GALT1-AS1 lncRNA/HuR [74,75] Epigenetic circFAT1/miR-375 [76] miR-625 [77] Gankyrin/ miR-200a [78] Post-translational FAT10 [79] ROCK2 [80–82] NF2 Mutation NF2 [83,84] Post-translational CD44 [85–88] Transcriptional SOX2 [89,90] LATS1/2 Protein Upregulation Tankyrase 1 [91] Epigenetic miR-100HG/EZH2 [92] Post-translational miR-302b/YOD1 [93] miR-34c/PLOD1 [94] Cancers 2022,14, 6211 5 of 30 Table 1. Cont. Sarcoma Subtype T-Sarcoma/ Non T-Sarcoma Hippo Member Deregulation Mechanism Deregulating Factors or Genetic Aberration References RASSF 4/5/10 Epigenetic Promoter hypermethylation [95,96] EwS YAP Transcriptional Interference EWSR1::FLI1 [69,97] T-Sarcoma TAZ Transcriptional Repression EWSR1::FLI1 [69,98] RASSF1/2 Epigenetic Promoter hypermethylation [69,99,100] EHE T-Sarcoma TAZ Chromosomal Rearrangement WWTR1::CAMTA1 [63,99–101] YAP Chromosomal Rearrangement YAP1::TFE3 [64,102] MLS T-Sarcoma YAP Transcriptional induction and nuclear localization FUS::DDIT3 [103,104] SEF and LGMFS (MUC4-) T-Sarcoma YAP Chromosomal Rearrangement YAP1::KMT2A [105–110] ARMS T-Sarcoma MST1 Protein inhibition by indirect fusion-dependent Mechanism PAX3::FOXO1-dependent upregulation of RASSF4 [14] RASSF1/5 Epigenetic Promoter hypermethylation [66,111,112] SRMS T-Sarcoma TEAD Chromosomal Rearrangement TEAD1::NCOA2 [113–116] VGLL2 Chromosomal Rearrangement VGLL2::NCOA2, VGLL2::CITED [113,117–119] SS T-Sarcoma MST1, MOB1 Protein inhibition by indirect fusion-dependent mechanism SS18::SSX-dependent IGF-II/IGF-IR signaling loop [120] non-FOSrearranged OB Non T-Sarcoma NF2 CNA NF2 homozygous deletion [121] UPS Non T-Sarcoma MST1/2 and LATS1/2 Post-translational and epigenetic Proteasomal degradation, deacetylated histones and hypermethylated promoters [122–124] AMOT Epigenetic Histone deacetylation [124] CS Non T-Sarcoma LATS1 and other kinases Post-translational PMRT1 [125] OFMT T-Sarcoma TAZ Chromosomal Rearrangement KDM2A::WWTR1 [126] ARMS: Alveolar Rhabdomyosarcoma; CS: Chondrosarcoma; EHE: Epithelioid Hemangioendothelioma; EwS: Ewing sarcoma; LGMFS: and Low-grade Fibromyxoid Sarcoma; MLS: Myxoid liposarcoma; OB: Osteoblastoma; OFMT: Ossifying fibromyxoid tumor; OS: Osteosarcoma; RMS: Rhabdomyosarcoma; SEF: Sclerosing Epithelioid Fibrosarcoma; SS: Synovial Sarcoma and UPS: Undifferentiated Pleomorphic Sarcoma. T-sarcoma: translocationassociated sarcomas; CNA: copy number alteration. Cancers 2022,14, 6211 6 of 30 Cancers 2022, 14, 6211 5 of 31 Figure 1. Regulation of the Hippo signaling pathway and main alterations of Hippo-pathway members reported in sarcomas. Green arrow lines and phosphates indicate induction of Hippo “ON” status, while red arrow lines and phosphates indicate “OFF” status. Alterations of the Hippo-pathway members are displayed with start symbols with colors denoting: transcriptional (green); posttranscriptional (pink); post-translational (yellow); epigenetic (blue), mutation/copy number alteration (orange) and chromosomal rearrangement (red) aberrations. An example of chromosomal rearrangement involving YAP1 and WWTR1 is showed in the figure (YAP1::TFE3 and WWTR1::CAMTA1). Table 1. Deregulation mechanisms of Hippo pathway in sarcomas. Sarcoma Subtype T-Sarcoma/ Non T-Sarcoma Hippo Member Deregulation Mechanism Deregulating Factors or Genetic Aberration References OS Non T-Sarcoma YAP Transcriptional H19 lncRNA/ Hedgehog signalling [72] SOX2 [73] Post-transcriptional B4GALT1-AS1 lncRNA/ HuR [74,75] Epigenetic circFAT1/ miR-375 [76] miR-625 [77] Gankyrin/ miR-200a [78] Post-translational FAT10 [79] ROCK2 [80–82] NF2 Mutation NF2 [83,84] Post-translational CD44 [85–88] Transcriptional SOX2 [89,90] LATS1/2 Protein Upregulation Tankyrase 1 [91] Epigenetic miR-100HG/EZH2 [92] Figure 1. Regulation of the Hippo signaling pathway and main alterations of Hippo-pathway members reported in sarcomas. Green arrow lines and phosphates indicate induction of Hippo “ON” status, while red arrow lines and phosphates indicate “OFF” status. Alterations of the Hippo-pathway members are displayed with start symbols with colors denoting: transcriptional (green); post-transcriptional (pink); post-translational (yellow); epigenetic (blue), mutation/copy number alteration (orange) and chromosomal rearrangement (red) aberrations. An example of chromosomal rearrangement involving YAP1 and WWTR1 is showed in the figure (YAP1::TFE3 and WWTR1::CAMTA1). 3.1. Osteosarcomas Osteosarcoma (OS) is the most common primary malignancy of bone and one of the most common primary malignant tumors in children and adolescents. OS can occur in any bone, with 75% of all cases occurring in the distal femur and proximal tibia [ 127 , 128 ]. OS is characterized by heterogeneous genetic complexity, including complex genomic rearrangements as well as copy number alterations [ 129 , 130 ]. In addition, aberrations in the Hippo pathway have been extensively reported, and the deregulation of several members of this signaling pathway is described as tumorigenic factors in OS. 3.1.1. YAP In 2013, Zhang et al. reported nuclear localization of YAP in OS patient tumor biopsies and that YAP1 knockdown inhibited the proliferation and invasion of OS cells by downregulation of the RUNX2 pathway [ 131 ]. The association between YAP nuclear localization and a poor prognosis in OS was reported by Bouvier et al., who suggested that the Hippo pathway could represent a therapeutic target in conventional OS [ 70 ]. Additionally, the transcription factor TEAD1 has been reported to be involved in YAP-driven OS development. Genetic silencing of TEAD1 suppresses several malignant phenotypes of OS cells, including cell proliferation, resistance to apoptosis, and invasiveness [ 132 ]. Interestingly, it Cancers 2022,14, 6211 7 of 30 has been shown that YAP and pSmad2 (a marker of active TGF β signaling) have potential prognostic value in canine appendicular OS [133]. YAP1 can be upregulated by Hedgehog (Hh) pathway activation. Chan L.H. et al. have reported that YAP1 was overexpressed in both human and mouse tumor tissues and that YAP1 expression was reduced by targeting the Hh signaling pathway. They also showed that the upregulation of the Hh signaling significantly prompted osteoblastic OS cells in mature osteoblasts. In addition, they described the aberrant expression of the long noncoding RNA (lncRNA), H19, and proved that its regulation was Hh signaling and YAP expression-dependent [72]. YAP can also be upregulated by the human HLA-F adjacent transcript 10 (FAT10) protein, a member of the ubiquitin-like protein family. It has been reported that FAT10 plays an essential role in developing malignant tumors and stabilizes YAP expression by modifying its ubiquitination and degradation. Moreover, this study revealed that FAT10 is overexpressed in OS, and in vivo and in vitro assays proved that FAT10 silencing inhibited OS proliferation [79]. A functional connection between Rho-associated coiled-coil containing protein kinase 2 (ROCK2) and YAP in regulating OS cell migration and metastasis formation has been described by Zucchini et al. They reported that ROCK2 silencing induced a reduction in the nuclear expression and transcriptional activity of YAP and significantly reduced tumor growth, and eradicated the metastatic potential of OS cell lines [ 80 ]. In this context, ROCK2 has been reported to be significantly upregulated in OS tissues compared with adjacent normal tissues. The expression level is related to tumor size and patient prognosis [ 81 , 82 ]. HuR, an RNA-binding protein, can also control YAP1 expression. Thus, Li Z. et al. showed that the expression of HuR is meaningfully increased in OS tissues and positively correlates with OS progression. Moreover, the knockdown of HuR suppressed OS cell migration and invasion, the epithelial-mesenchymal transition (EMT) process, and the stemness of OS cells. Mechanistically, it was proved that HuR directly binds to YAP1 mRNA, stabilizing and increasing its transcriptional activity. Significantly, HuR and YAP1 expression was positively correlated in OS tissues [ 74 ]. A similar study by Xu, W., et al. revealed that the expression of the lncRNA, B4GALT1-AS1, was considerably increased in OS tissues. B4GALT1-AS1 was found to recruit HuR to enhance YAP1 mRNA stability and its transcriptional activity. B4GALT1-AS1 knockdown repressed proliferation, migration, and stemness of OS cells. Importantly, in vitro and in vivo assays of YAP1 overexpression rescued the inhibition of B4GALT1-AS1 knockdown on OS cell progression [75]. Liu G. et al. have observed significant upregulation of circFAT1, a circular RNA originating from exon two of the FAT1 gene, in human OS tissues and cell lines. In this study, the in vitro inhibition of circFAT1 efficiently prevented the migration, invasion, and tumorigenesis of OS cells and repressed in vivo OS growth. Mechanistic studies showed that circFAT1 could sponge microRNA-375 (miR-375), which was found to be downregulated in OS tissues and cell lines. Furthermore, they described that YAP1 3 0 -UTR mRNA is directly targeted by miR-375, revealing other potential regulatory properties of the circularized protein-coding exons or “sponging miRNAs” and providing a new therapeutic target for the OS treatment [76]. Luo Y. et al. described the upregulated expression of miR-624-5p in OS cells and tissues. A higher malignant phenotype of OS was observed when overexpressing miR-624-5p in in vitro and in vivo assays. In addition, they revealed that the expression of the protein tyrosine phosphatase receptor type B (PTPRB) was negatively correlated and identified the Hippo signaling pathway to be involved in the miR-624-5p/PTPRB axis, although precise mechanisms demand further research [134]. An opposite role to that described for miR-624-5p has been reported for miR-625. Luo Z. et al. revealed that miR-625 was markedly downregulated in OS tissues and cell lines. Mechanistically, they showed that miR-625 mimic attenuated the cell proliferation and invasion of OS cells by directly binding to YAP1 3 0 -UTR mRNA and suppressing YAP1 Cancers 2022,14, 6211 8 of 30 expression. Furthermore, YAP1 upregulation rescued the inhibitory properties of miR-625 on OS cell proliferation and invasion [77]. Cheng L. et al. have shown that Gankyrin, a regulatory subunit of the proteasome complex, is upregulated in OS and predicts disease progression and poor prognosis. Mechanistic studies revealed that gankyrin avoids YAP1 downregulation mediated by miR-200a through P53 and origins a positive feedback loop to regulate YAP signaling in OS cells. Furthermore, in vitro and in vivo studies showed that gankyrin interacts with YAP to induce OS tumorigenesis [78]. 3.1.2. NF2 NF2 has also been described as playing a role in OS development. In human, germline or somatic mutations in one allele of NF2 results in the disease neurofibromatosis type 2, which is associated with schwannomas, meningiomas, and ependymomas. Nevertheless, heterozygous Nf2 mutant mice develop mainly osteomas and OS [83,84]. NF2 activity depends on specific interaction with the cytoplasmic tail of CD44, a transmembrane hyaluronate receptor that functions as an upstream regulator sensing the extracellular environment to modulate ERK, AKT, and Hippo pathways [ 85 , 86 ]. A study carried out by Gvozdenovic A. et al. revealed that CD44 silencing in OS cells reduces the number of proliferative cells and decreases the content of NF2 protein. However, in vivo studies showed that OS cells with reduced CD44 expression enhanced the malignant phenotype when compared to control cells. They suggested that the apparent discrepancy between in vitro and in vivo results highlights the critical impact of the tumor environment on OS progression [ 87 ]. A recent study has identified increased levels of total CD44 mRNA and membrane localization of CD44 in primary and metastatic OS compared to normal bone. In addition, they showed that CD44 promotes transendothelial migration of tumor OS cells [88]. Some studies have proven that Hippo signaling dysregulation is associated with SOX2 level in OS. Basilico et al. described that SOX2 maintains cancer stem cells (CSC) in OS and antagonizes the Hippo pathway by directly repressing two Hippo activators, NF2 and WWC1, leading to exaggerated YAP function. Moreover, this study showed the requirement of SOX2 for OS formation and survival of the tumor cells, proposing that disruption of these pathways initiated by SOX2 is an attractive strategy for the treatment of OS [ 89 , 90 ]. In addition, it has been described that YAP can regulate the expression of SOX2 by interacting with TEAD on two TEAD-binding DNA elements near the SOX2 gene. Thus, SOX2 and YAP reinforce each other’s expression to maintain stemness and tumorigenicity in OS [ 73 ]. The crucial role of SOX2 in OS was likewise described by Upal Basu-Roy et al., who reported that thiazolidinedione drugs (TZDs), a class of small-molecule activators of PPAR γ , decrease the expression of target genes of YAP with a simultaneous reduction in SOX2 and YAP nuclear localization. They demonstrated that TZDs target the PPAR γhigh - expressing CSC population and restores the tumor-suppressive Hippo signaling effects in OS [135]. 3.1.3. LATS1/2 A recent study showed that the inhibition of Tankyrase 1 (TANK1), classified as a positive regulator of telomere length, by antisense oligodeoxynucleotides (TANK1-ASODN) decreased cell growth, migration, invasion, and EMT in OS cells. Mechanistically, the inhibition of TANK1 expression modulated the Hippo/YAP signaling, inducing significantly LATS1 expression and, subsequently, YAP phosphorylation [91]. Another study by Su X. et al. showed the overexpression of the miR-100HG in OS tissues and cell lines and the correlation with poor prognosis for OS patients. Inhibition of OS progression was observed after a miR-100HG knockdown by reducing cell proliferation, cell cycle distortion, and apoptosis resistance. Mechanism investigation revealed that miR-100HG exerted oncogenic function in OS by inactivating the Hippo signaling pathway. Concretely, RNA immunoprecipitation assay revealed the binding between miR-100HG Cancers 2022,14, 6211 9 of 30 and EZH2 in OS cells, suggesting that the expression of miR-100HG downstream targets is inhibited by epigenetic mechanisms involving EZH2. Further experiments revealed that both miR-100HG and EZH2 knockdown significantly upregulated the LATS1/2 expression in OS cells. Finally, ChIP assay results showed that EZH2 binding to the LATS1/2 promoter is inhibited by miR-100HG silencing, and consequently, a reduction of H3K27 trimethylation is displayed [92]. A more recent study developed by the same research group has reported that the deubiquitinase YOD1, which stabilizes ITCH (Itchy E3 Ubiquitin Protein Ligase) and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, was highly expressed in OS cells. They described that overexpression of miR-302b decreased the mRNA expression of YOD1 (direct target of miR-302b), ICTH, and YAP1. In contrast, LATS1 expression increased, suggesting that the YOD1-ICTH-LATS1-YAP axis is controlled by miR-302b [93]. Wu X. et al. described that the upregulation of the lysyl hydroxylase PLOD1 was correlated with the progression and worse survival probability of OS patients. Moreover, PLOD1 overexpression promoted OS tumorigenesis and metastasis in vitro and in vivo , and the mRNA levels of CTGF and CYR61 were significantly upregulated. In contrast, protein levels of p-LATS1 and p-YAP were decreased without disturbing p-MST1/2. Mechanistically, they proved that PLOD1 is directly regulated by miR-34c and PLOD1 mRNA, and miR-34c levels negatively correlated in OS samples [94]. 3.1.4. RASSF Three RASSFs (RASSF4, RASSF5, and RASSF10) proteins have been identified as tumor suppressors in OS. RASSF5 and RASSF10 have been reported to be epigenetically inactivated by hypermethylation of their CpG island promoters in OS. In vitro experiments in OS cell lines proved that overexpression of RASSF4 significantly inhibited proliferation, migration, and invasion as well as the EMT process [ 95 ], and RASSF5 overexpression markedly suppressed cell proliferation and invasion and induced cell apoptosis through activation of the MST1/LATS1 pathway [96]. 3.1.5. TAZ Interestingly, although there is not much data on the potential role of TAZ on OS tumorigenesis, some studies link TAZ and miRNAs to OS oncogenic behavior. Thus, Ma J. et al. demonstrated the upregulation of TAZ in OS tissues and cell lines, and OS cell migration, invasion, and proliferation could be induced by TAZ overexpression. The mechanistic study revealed that TAZ overexpression leads to miR-224 upregulation, which inhibits the tumor suppressor SMAD4 [ 136 ]. Similar findings were reported by Shen S. et al., which described that TAZ is upregulated in OS and modulates EMT. They demonstrated that TAZ induces miR-135b and suppresses the expression of LATS2,APC, and GSK-3 β [ 137 ]. 3.2. Ewing Sarcoma Ewing sarcoma (EwS) is the second most frequent primary bone tumor and affects mainly children and young adolescents. EwS is characterized by gene fusions between EWSR1 and members of the ETS gene family (usually FLI1), which are considered the main oncogenic driver of the disease, but exhibit a low somatic mutation rate, and secondary genetic alterations are uncommon [ 61 , 138 ]. No recurrent genetic alterations in members of the Hippo pathway have been described in EwS. Instead, aberrant activation of TAZ and YAP has been observed in several studies, and we have shown that it associates with poor patient prognosis [ 67 , 69 , 98 , 139 ]. Moreover, TAZ and YAP suppression negatively affects proliferation and invasion capacity in EwS cell lines, and YAP could also mediate resistance to contact inhibition [69,140]. Interestingly, we described a transcriptional antagonism between the fusion EWSR1::FLI1 and YAP/TAZ [ 69 ], which may underlay the phenotypic plasticity of EwS cells. Franzetti G.A. et al. proposed that this plasticity relies on the expression levels of the fusion protein, with low levels favoring a migratory phenotype and, therefore, the dissemination Cancers 2022,14, 6211 16 of 30 Table 2. Cont. Small Molecule Sarcoma Phase ClinicalTrials.gov Identifier Status Pazopanib Recurrent Uterine Corpus Sarcoma and other tumors II NCT01247571 Completed with results Advanced Angiosarcoma III NCT02979899 Completed with results Surgically and metastatic LPS II NCT01506596 Completed with results Advanced/ Metastatic LPS II NCT01692496 Completed with results CS, Metastatic CS II NCT01330966 Completed with results Solid Tumors II NCT01956669 Completed with results Solid Tumor I NCT01468922 Completed with results Metformin OS, EwS II NCT04758000 Recruiting CS and other tumors I/II NCT02496741 Completed Angiosarcoma and other tumors II NCT01042379 Recruiting IK-930 Adult Solid Tumor, EHE, Solid Tumors With YAP1/TAZ Fusion Genes, NF2 Deficiency or YAP1 or TAZ Gene Fusions, and other tumors I NCT05228015 Recruiting ASPS: Alveolar Soft Part Sarcoma; CCS: Clear Cell Sarcoma; DSRCT: Desmoplastic Small Round Cell Tumor; EMCS: Extraskeletal Myxoid Chondrosarcoma; ERMS: Embryonal Rhabdomyosarcoma; FS: Fibrosarcoma; GIST: Gastrointestinal Stromal Tumor; GSCB: Giant Cell Tumor of Bone; HPC: Hemangiopericytoma; LMS: Leiomyosarcoma; LPS: Liposarcoma; PNST: Malignant Peripheral Nerve Sheath Tumor. Not Applicable (NA). All clinical trials, except withdrawn, with dasatinib, statins, metformin in sarcoma patients are listed. Only completed with results clinical trials using pazopanib are shown. Phase is used to describe trials without FDAdefined phases, including trials of devices or behavioral interventions as described in https://clinicaltrials.gov/. 4.1. Inhibition of YAP-TEAD Interaction: Verteporfin The most used molecule is verteporfin, a benzoporphyrin-derived compound that has been approved by the FDA for the photodynamic treatment of age-related neovascular macular degeneration [ 181 ]. Verteporfin is the only reported direct inhibitor of YAP/TAZ. It was described that verteporfin binds to YAP and changes its conformation, inhibiting the binding of YAP-TEAD [ 182 ]. Later, it was reported that verteporfin increases 14-3-3 σ levels, which promotes the translocation of YAP from nuclear to cytoplasm, decreasing its transcriptional co-activation function [ 183 ]. A recent study has revealed a mechanism by which the function of YAP is inhibited by verteporfin by regulating YAP SUMOylation in endometrial cancer. They also described that Serine127 phosphorylation of YAP is important for YAP sumo modification [184]. At the transcriptional level, verteporfin has been described to reduce the expression of Hippo pathway targets genes, and in vitro and in vivo studies have proven that verteporfin decrease proliferation and migration, and invasion of certain cancer cells [ 182 , 185 – 190 ], including EwS and SS cells [ 98 , 120 ]. Furthermore, Visudyne, the FDA-approved liposomal formulation of verteporfin, is being tested in some clinical trials, such as the treatment of cutaneous metastases of breast cancer [191]. 4.2. YAP/TAZ Cytoplasmic Retention: Dasatinib, Statins, Pazopanib, and Metformin A small molecule screening carried out by Oku et al. in 2015 showed that dasatinib, statins, and pazopanib inhibited the nuclear localization of YAP/TAZ and TEAD-dependent transcription, and induced YAP/TAZ phosphorylation in breast cancer cell lines [192]. Dasatinib was originally described as an SRC kinase inhibitor and then shown to inhibit Bcr-Abl and other tyrosine kinases. It has been reported that dasatinib blocks cell migration and invasion in many diverse human sarcoma cell lines and induces apoptosis in the bone sarcoma subgroup through inhibition of SRC-mediated signaling [ 193 ]. Numerous studies have reported that YAP and TAZ can be activated and stabilized by SRC-family kinases -mediated phosphorylation [ 60 ]. Dasatinib has shown antitumor ef- Cancers 2022,14, 6211 17 of 30 ficacy in several types of sarcomas, including alveolar soft part sarcoma (ASPS) [ 194 ], uterine leiomyosarcoma (LMS) [ 195 ], neuroblastoma, EwS [ 69 , 196 ], childhood RMS [ 112 ] and uterine sarcoma [ 197 ]. Indeed, dasatinib is being tested in several clinical trials in cancer, highlighting chronic myeloid leukemia [ 198 – 200 ], acute lymphoblastic leukemia in adults [201], metastatic breast carcinoma [202], lung cancer [203,204], and several types of sarcomas [205–209]. Statins are reductase-competitive inhibitors that are commonly used to treat hypercholesterolemia by inhibiting the mevalonate pathway. They function by suppressing hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductases, the rate-limiting enzymes in the synthesis of a fatty acid intermediate named mevalonate [ 210 ]. Aberrant inactivation of the mevalonate pathway has been reported to promote tumor progression and has a marked negative effect on YAP/TAZ transcriptional activity, as YAP/TAZ actions need mevalonate, geranylgeranyl pyrophosphate (GGPP) and Rho GTPases [ 30 ]. Many studies have demonstrated that statin use could exhibit potential survival benefits for cancer patients and appeared to be very promising in combined therapies, as they have been shown to reduce the resistance of cancer cells to other anti-cancer drugs [ 210 – 214 ]. Statin antitumoral effects have also been demonstrated in fibrosarcoma and OS cell lines [ 215 , 216 ]. Accordingly, a protective role in breast-cancer-related mortality [ 214 ], an improvement in ovarian cancer survival and multiple myeloma [ 217 , 218 ], and a reduction of the risk of developing lethal prostate cancer [ 219 ] have been observed among statin users. In this same context, a strong association between preoperative statin therapy and reduced postoperative mortality following surgical resection for rectal cancer has been reported [ 220 ]. Furthermore, statin treatment in chronic obstructive pulmonary disease (COPD) may reduce the risk of lung cancer [ 221 ]. Consequently, statins are being tested in several cancer clinical trials, such as oesophageal adenocarcinoma [222] and rectal cancer [223]. Pazopanib is a c-KIT, FGFR, PDGFR, and VEGFR multi-kinase inhibitor, but it has also been proved that it induces proteasomal degradation of YAP and TAZ [ 192 , 224 – 226 ]. Pazopanib has shown potent antitumor activity in many cancer cells [ 224 , 227 – 229 ] and is being tested in a myriad of clinical trials as an anti-cancer therapy for lung [ 230 ], ovarian [ 231 – 233 ], prostate [ 234 ], renal cell carcinoma [ 235 ], urothelial [ 236 ], and several types of sarcomas [237–248]. It is well-known that Metformin (MET) stimulates AMP-activated protein kinase (AMPK) and is widely used for the treatment of hyperglycemia. However, recent studies have described that MET interferes with the Hippo signaling pathway. Wu et al. have reported that MET activates the AMPK α , which alters the YAP/TEAD4/CCNE1/2 axis signaling, inducing cell cycle arrest and reducing cell growth of bladder cancer cells [249]. Jin et al. showed that MET controls miR-381/YAP activity and reduces the malignant phenotype of non-small cell lung cancers (NSCLCs) cells [ 250 ]. Another mechanism has been reported by Liu et al. where MET induces activation of the Hippo pathway through Scribble (SCRIB). Upregulation of SCRIB expression recruits MST1/2 and LATS1 to the plasma membrane, leading to YAP phosphorylation and its retention within the cytoplasm and finally inhibiting cell proliferation and invasion in human breast cancer cell lines [ 251 ]. Another recent study described that MET treatment downregulated YAP/TAZ expression and enhanced YAP phosphorylation in melanoma cells [ 252 ]. Thus, recent studies have examined the potential use of MET in cancer patients to decrease tumor growth, reduce the risk of cancer and improve prognosis [ 253 – 255 ]. The anti-cancer effects of MET treatment have also been observed in several types of sarcoma cell lines, such as OS [ 256 – 260 ], EwS [ 259 , 261 ], RMS [ 259 , 262 ], and endometrial [ 263 ]. In addition, MET is currently under several clinical trials in cancer, including colorectal [ 264 ], endometrial [ 265 ], ovarian [ 266 ], esophageal [267], and CS [268]. 4.3. Inhibition of TEAD-Transcription Activity TEAD transcription factors (TEAD1-4), as the downstream effectors for YAP/TAZ activity, are very attractive therapeutic targets to disturb Hippo-induced transcriptional Cancers 2022,14, 6211 18 of 30 activity. They are composed of two well-structured and conserved domains, the YAPbinding domain (YBD) and the DNA binding domain (DBD), separated by a proline-rich region [ 269 ]. The YBD is stabilized by S-palmitoylation and is required for its function in hippo pathway signaling [ 270 ]. Thus, TEAD lipidation status is a regulator of protein homeostasis, and its modulation can be regulated by small molecules [271,272]. Remarkably, a small molecule inhibitor of TEAD, IK-930, that prevents palmitate binding has been very recently described. In preclinical models, IK-930 demonstrates antitumor activity in mouse xenograft models with Hippo pathway genetic alterations such as NF2 deficiency and gene fusion involving YAP1 and WWTR1. IK-930 is under clinical investigation, Phase 1, as an oral TEAD inhibitor agent in patients with advanced solid tumors. This study began in January 2022 and is currently recruiting [273]. 5. Conclusions The Hippo pathway signaling represents a potential opportunity for cancer treatment. As has been discussed in this review, the Hippo pathway is dysregulated in many types of sarcomas and has been associated with tumor progression, malignancy, and poor prognosis. The research efforts for unveiling the Hippo pathway implications in sarcoma development and clinical behavior will provide new therapeutic insights. The identification of new drugs targeting this signaling pathway is, to date, a challenge for pharmaceutical companies and the sarcoma community. Author Contributions: C.S.-A., J.O.-P., A.T.A., E.d.Á. and J.D.-M. designed and wrote the manuscript; J.D.-M. and E.d.Á. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: E.d.Á.’s laboratory is supported by ISCIIIFEDER (PI20/00003) to E.d.Á., Consejería de Salud y Familias, Junta de Andalucía (PE-0186-2018) to E.d.Á. and (PI-0061-2020) to C.S.-A. and E.d.Á., GEIS (Beca JoséMaría Buesa) to A.T.A., GEIS-Fundación Mari Paz Jiménez Casado (Beca Trienal a la Investigación en Sarcomas) to J.D.-M., Fundación CRIS Contra el Cáncer, Asociación Pablo Ugarte, Fundación María García Estrada and CIBERONC. C.S.-A. is supported by the European Social Fund and the Junta de Andalucía (Talento Doctores 2020, DOC_01473), J.O.-P. is granted by a pre-doctoral fellowship from the VI Plan Propio from the Universidad de Sevilla; A.T.A. is supported Juan de la Cierva Incorporación fellowship (IJC-2018-036767-I), and J.D.-M. is supported by CIBERONC (CB16/12/00361). Conflicts of Interest: The authors declare no conflict of interest. References 1. Pan, D. The Hippo Signaling Pathway in Development and Cancer. Dev. Cell 2010,19, 491–505. [CrossRef] [PubMed] 2. 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