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

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2015

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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.

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10.3389/fonc.2015.00190

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Deel, Michael D, Jenny J Li, Lisa ES Crose and Corinne M Linardic (2015). A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas. Front Oncol, 5. p. 190. 10.3389/fonc.2015.00190 Retrieved from https://hdl.handle.net/10161/15190.

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Scholars@Duke

Deel

Michael D Deel

Assistant Professor of Pediatrics

Dr. Deel is a clinician scientist in Pediatric Hematology/Oncology. In addition to caring for pediatric patients with hematologic disorders or malignancy, his research focuses on finding novel ways to target fusion-positive pediatric sarcomas. His current work focuses on understanding the gene regulation and molecular pathways responsible for alveolar rhabdomyosarcoma, which is among the most difficult to cure pediatric cancers. Alveolar rhabdomyosarcoma is driven by chromosomal translocations t(2;13) or t(1;13) that result in oncogenic transcription factors encoding for PAX3/7-FOXO1 fusion proteins. The PAX3/7-FOXO1 oncogenes are currently not viable therapeutic targets. Using a variety of cell culture and murine models, Dr. Deel is investigating genes and pathways that regulate or coordinate PAX3/7-FOXO1-mediated tumorigenesis.

Linardic

Corinne Mary Linardic

Associate Professor of Pediatrics

Pediatric Sarcomas: Sarcomas are among the most difficult-to-treat cancers in pediatric oncology, with metastatic forms having the highest mortality. We have established genetically defined human cell-based models and genetically engineered murine models for the pediatric skeletal muscle cancer known as rhabdomyosarcoma. Using these models, we can study the causative role of certain genetic changes (e.g. chromosomal translocations and oncogenic RAS) in rhabdomyosarcoma formation and treatment resistance. Specific goals of this research program include the identification of signaling pathways corrupted in rhabdomyosarcoma, with focus on the PAX3-FOXO1 mutation and its downstream effectors and oncogenic RAS, and identification of new therapeutic targets for treatment of this childhood cancer.


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