<scp>WNT</scp> signaling in bone development and homeostasis

Zhong, Zhendong; Ethen, Nicole J.; Williams, Bart O.

doi:10.1002/wdev.159

Cited by 109 publications

(80 citation statements)

References 102 publications

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“…The combined results of these studies demonstrate that activation of canonical Wnt/beta-catenin signaling, by ligands in the tumor microenvironment, results in more clinically aggressive disease. In keeping with the microenvironment being the source of Wnt/beta-catenin activation in these tumors, recurrent somatic mutations in the pathway are rare (2-4, 15) and Wnt and RSPO ligands are highly expressed in developing bone, the predominant site of Ewing tumors in pediatric and young adult patients (37, 38). Mechanistically, our data show that the aggressive clinical phenotype of Wnt/beta-catenin-activated tumors is mediated, at least in part, by a paradoxical antagonism of EWS/ETS-dependent transcription, which results in activation of metastasis-associated genes that are normally subject to EWS/ETS-dependent repression.…”

Section: Discussionmentioning

confidence: 99%

Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States

et al. 2016

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Ewing sarcomas are characterized by the presence of EWS/ETS fusion genes in the absence of other recurrent genetic alterations and mechanisms of tumor heterogeneity that contribute to disease progression remain unclear. Mutations in the Wnt/beta-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis. We evaluated beta-catenin and LGR5 expression in Ewing sarcoma cell lines and tumors and noted marked intra- and inter-tumor heterogeneity. Tumors with evidence of active Wnt/beta-catenin signaling were associated with increased incidence of tumor relapse and worse overall survival. Paradoxically, RNA sequencing revealed a marked antagonism of EWS/ETS transcriptional activity in Wnt/beta-catenin activated tumor cells. Consistent with this, Wnt/beta-catenin activated cells displayed a phenotype that was reminiscent of Ewing sarcoma cells with partial EWS/ETS loss of function. Specifically, activation of Wnt/beta-catenin induced alterations to the actin cytoskeleton, acquisition of a migratory phenotype and up regulation of EWS/ETS-repressed genes. Notably, activation of Wnt/beta-catenin signaling led to marked induction of tenascin C (TNC), an established promoter of cancer metastasis, and an EWS/ETS-repressed target gene. Loss of TNC function in Ewing sarcoma cells profoundly inhibited their migratory and metastatic potential. Our studies reveal that heterogeneous activation of Wnt/beta-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing sarcoma. Significantly, this is mediated, at least in part, by inhibition of EWS/ETS fusion protein function that results in de-repression of metastasis-associated gene programs.

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Section: Discussionmentioning

confidence: 99%

Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States

et al. 2016

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“…Extensive studies in the area during the past several decades have mostly focused on endocrine or paracrine signaling as well as transcriptional regulation [1, 2]. Those studies have uncovered the critical roles of growth factors such as Wnt proteins and transcription factors including Runx2, Osterix and ATF4 during osteoblast differentiation [3–8]. However, relatively little is understood about how osteoblasts fulfill their key function of active protein synthesis and matrix secretion, a process highly demanding not only in building blocks but also in energy [9].…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling and cellular metabolism in osteoblasts

Karner

Long

2016

Cell. Mol. Life Sci.

226

180

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The adult human skeleton is a multifunctional organ undergoing continuous remodeling. Homeostasis of bone mass in a healthy adult requires an exquisite balance between bone resorption by osteoclasts and bone formation by osteoblasts; disturbance of such balance is the root cause for various bone disorders including osteoporosis. To develop effective and safe therapeutics to modulate bone formation, it is essential to elucidate the molecular mechanisms governing osteoblast differentiation and activity. Due to their specialized function in collagen synthesis and secretion, osteoblasts are expected to consume large amounts of nutrients. However, studies of bioenergetics and building blocks in osteoblasts have been lagging behind those of growth factors and transcription factors. Genetic studies in both humans and mice over the past fifteen years have established Wnt signaling as a critical mechanism for stimulating osteoblast differentiation and activity. Importantly, recent studies have uncovered that Wnt signaling directly reprograms cellular metabolism by stimulating aerobic glycolysis, glutamine catabolism as well as fatty acid oxidation in osteoblast-lineage cells. Such findings therefore reveal an important regulatory axis between bone anabolic signals and cellular bioenergetics. A comprehensive understanding of osteoblast metabolism and its regulation is likely to reveal molecular targets for novel bone therapies.

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“…This suggests that angiogenesis plays a crucial role in the reparative process. In addition, the Wnt signaling pathway, which has been reported to play a pivotal role in regulating the balance between bone formation and bone resorption (Zhong et al, 2014;Wang, X. et al, 2014;Wang, Y. et al, 2014), was enriched in our results. We believe this pathway could be responsible for some of the pathological changes observed in the reparative interface, and may provide an avenue for therapeutic intervention, warranting further investigation.…”

Section: Discussionmentioning

confidence: 50%