The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

Tremblay, Annie; Missiaglia, Edoardo; Galli, Giorgio; Hettmer, Simone; Urcia, Roby; Carrara, Matteo; Judson, Robert N.; Thway, Khin; Nadal, Gema; Selfe, Joanna; Murray, Graeme I.; Calogero, Raffaele; Bari, Cosimo De; Zammit, Peter S.; Delorenzi, Mauro; Wagers, Amy J.; Shipley, Janet; Wackerhage, Henning; Camargo, Fernando D.

doi:10.1016/j.ccr.2014.05.029

Cited by 160 publications

(216 citation statements)

References 52 publications

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“…Both genetic and pharmacologic inhibition of YAP/TEAD and FOXM1 result in sarcoma cell proliferation defects, suggesting that these targets represent promising therapeutic interventions for mesenchymal tumors. Very recent studies have shown that YAP overexpression and function plays a role in the pediatric malignancies alveolar embryonal rhabdomyosarcoma (aRMS) and embryonal rhabdomyosarcoma (eRMS) (23,24). Together with these findings, we conclude that the Hippo pathway is potentially important in multiple sarcoma subtypes.…”

supporting

confidence: 51%

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Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

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supporting

confidence: 51%

“…4F). We were particularly intrigued by our findings in the rhabdomyosarcoma cell line, because recent reports have implicated Hippo pathway perturbations here (23,24). YAP expression has been shown to be elevated in these tumors compared with normal tissue and to promote tumor growth in this context.…”

Section: Injection We Minimizedmentioning

confidence: 89%

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although mutations in the Hippo pathway are rare, mutation or deletion of Lats2 is significant in malignant mesothelioma (16). Furthermore, the oncoprotein YAP has been implicated in promoting the formation of several types of tumors, such as liver and skin tumors and rhabdomyosarcoma (17)(18)(19)(20)(21). As expected, overexpression or hyperactivation (nuclear localization) of YAP is frequently detected in several human malignancies, including liver, ovarian, breast, lung, and pancreatic cancer (18)(19)(20)(22)(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 93%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

142

151

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f Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). P rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1, 2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known. It is expected that understanding the molecular mechanisms and identifying the molecular pathways underlying the acquisition of castration resistance in prostate cancer are critical for the design of therapeutic strategies and may lead to the discovery of novel targets.The Hippo signaling pathway, originally defined by fly geneticists, plays an important role in tumorigenesis by regulating cell proliferation and apoptosis (3-7). In mammals, protein kinases Mst1/2 (mammalian sterile 20-like 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2) and the adaptor proteins WW45 (WW domain-containing protein) and Mob1 (Mps one binder 1) are the Hippo core components. These proteins form complexes to regulate their activity mainly through phosphorylation. The Hippo core is tumor suppressive and exerts its function by phosphorylating and inactivating YAP (Yes-associated protein) and its paralog, TAZ (transcriptional coactivator with a PDZ-bi...

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“…Because the very character of each experiment results in tumorigenesis or no tumorigenesis, any untested variable may be the key between the 2 potential results. For example, elegant work by others has recently demonstrated that the sarcomagenesis-originating potential of satellite cells in particular depends on their activation in response to injury (37,38). Our experiments did not address the application of this principle to synovial sarcomagenesis, but future work should.…”

Section: Discussionmentioning

confidence: 97%

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

Barrott¹,

Illum²,

Jin³

et al. 2017

Journal of Clinical Investigation

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were performed using a 2-tailed Student's t test, with a P value of less than 0.05 considered significant.Study approval. All mouse experiments were conducted with the approval of the IACUC of the University of Utah and in accordance with international legal and ethical standards. Clinical analyses were performed with approval from the IRB of the University of Utah and in accordance with legal and ethical standards. As only extant records were reviewed, the requirement for consent was waived by the IRB. Author contributionsKBJ and MLH conceived the experiments. JJB, BEI, HJ, MLH, YW, MH and KBJ performed experiments. JJB, AG, and KBJ analyzed data. MRC contributed mice and resources. KBJ wrote the manuscript, and all authors edited it.

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The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

Cited by 160 publications

References 52 publications

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

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