Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Shah, Sagar; David, Justin M.; Tippens, Nathaniel D.; Mohyeldin, Ahmed; Martínez-Gutiérrez, Juan Carlos; Ganaha, Sara; Schiapparelli, Paula; Hamilton, Duane H.; Palena, Claudia; Levchenko, Andre; Quiñones‐Hinojosa, Alfredo

doi:10.1016/j.celrep.2017.09.057

Cited by 60 publications

(56 citation statements)

References 90 publications

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“…Yes-associated protein (YAP), an effector of the Hippo pathway and a master regulator of organ development (41), was recently found to be directly transactivated by BRACHYURY in chordoma cells through binding to the proximal region of the YAP promoter. Interestingly, BRACHYURY regulates YAP signaling through a non-transcriptional mechanism in lung carcinoma (18). Both BRACHYURY and YAP expressions were found to be elevated in glioblastoma and brain metastases originating from lung carcinomas, and BRACHYURY knockdown resulted in a significant decrease in YAP protein and mRNA expression in primary glioblastoma cells.…”

Section: Downstream Regulatory Network By Brachyury Activationmentioning

confidence: 99%

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

Chen

Zhang

et al. 2020

Front. Oncol.

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Transcription factor brachyury, with a DNA-binding T-domain, regulates posterior mesoderm formation and notochord development through binding with highly conserved palindromic consensus sequence in a variety of organisms. The absence of brachyury expression in majority of adult normal tissues and exclusive tumor-specific expression provides the potential to be developed into a novel and promising diagnostic and therapeutic target in cancer. As a sensitive and specific marker in the diagnosis of chordoma, brachyury protein has been verified to involve in the process of carcinogenesis and progression of chordoma and several epithelial carcinomas in various studies, but the mechanism by which brachyury promotes tumor cells migrate, invade and metastasis still remains less clear. To this end, we attempt to summarize the literature on the upstream regulatory pathway of brachyury transcription and downstream controlling network by brachyury activation, all of which involve in both the embryonic development and tumor progression. We present the respective correlation of brachyury expression with tumor progression, distant metastasis, survival rate and prognosis in several types of tumor samples (including chordoma, lung cancer, breast carcinoma, and prostate cancer), and various brachyury gain-of-function and loss-of-function experiments are summarized to explore its specific role in respective tumor cell line in vitro. In addition, we also discuss another two programs relating to brachyury function: epithelial-to-mesenchymal transition (EMT) and cell cycle control, both of which implicate in the regulation of brachyury on biological behavior of tumor cells. This review will provide an overview of the function of master transcriptional factor brachyury, compare the similarities and differences of its role between embryonic development and carcinogenesis, and list the evidence on which brachyury-target therapies have the potential to help control advanced cancer populations.

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Section: Downstream Regulatory Network By Brachyury Activationmentioning

confidence: 99%

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

Chen

Zhang

et al. 2020

Front. Oncol.

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“…Instead, YAP/TAZ are often overexpressed and highly accumulated in the nuclei in cancer cells [ 107 , 109 ]. This phenotype is preserved in many cancer tissues [ 110 – 113 ]. Apparently, YAP/TAZ overexpression promotes transcription of YAP/TAZ target genes [ 114 , 115 ].…”

Section: Yap/taz In Cancermentioning

confidence: 99%

Mechanoregulation and pathology of YAP/TAZ via Hippo and non‐Hippo mechanisms

Dobrokhotov¹,

Samsonov²,

Sokabe³

et al. 2018

Clinical & Translational Med

122

105

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Yes-associated protein (YAP) and its paralog WW domain containing transcription regulator 1 (TAZ) are important regulators of multiple cellular functions such as proliferation, differentiation, and survival. On the tissue level, YAP/TAZ are essential for embryonic development, organ size control and regeneration, while their deregulation leads to carcinogenesis or other diseases. As an underlying principle for YAP/TAZ-mediated regulation of biological functions, a growing body of research reveals that YAP/TAZ play a central role in delivering information of mechanical environments surrounding cells to the nucleus transcriptional machinery. In this review, we discuss mechanical cue-dependent regulatory mechanisms for YAP/TAZ functions, as well as their clinical significance in cancer progression and treatment.

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“…23 Recent studies indicate that VP is also a potent inhibitor of Yes-associated protein (YAP), a key transcriptional coactivator of the Hippo pathway and has been shown to operate as an oncoprotein in cancers. 24 With YAP being overactive in cancerous tissues, we postulated that VP could show cytotoxic effects to a greater degree on GBM cells in comparison to healthy brain stromal cells, 7,10,12,[25][26][27] as was previously shown for multiple cancers, including pancreatic, small cell lung cancer, triplenegative breast cancer, and brain cancer. 21,[28][29][30][31] In this study, we encapsulated VP in a micelle vehicle composed of poly(ethylene glycol)-poly(β-amino ester)poly(ethylene glycol) (PEG-PBAE-PEG) triblock copolymer.…”

Section: Introductionmentioning

confidence: 82%

“…6 Mechanical and chemical signaling promotes recurrence of the tumor and it is difficult to overcome the elaborate pathways and signals involved to attenuate further invasive growth of the tumor. [7][8][9][10][11][12] After resection, it has been suggested that the tumor cells undergo a shift to a more drug-resistant state, preventing commonly used chemotherapeutic drugs such as temozolomide (TMZ) from having a significant therapeutic effect. 13,14 Therefore, new therapeutics as well as new technologies able to deliver high drug doses to brain tumor cells are needed to provide long-term protection of the microenvironment and prevent tumor recurrence.…”

Section: Introductionmentioning

confidence: 99%

<p>Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics</p>

Shamul

Shah

Kim

et al. 2019

IJN

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Background: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease-and therapyspecific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting. Methods: Biodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells. Results: For anisotropic micelles, uptake efficiency was~100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (~1.8-fold greater, p ≤ 0.001) and 24 hrs (~2.1-fold greater, p ≤ 0.0001). Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.

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Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Cited by 60 publications

References 90 publications

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

The Roles of Embryonic Transcription Factor BRACHYURY in Tumorigenesis and Progression

Mechanoregulation and pathology of YAP/TAZ via Hippo and non‐Hippo mechanisms

<p>Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics</p>

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