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  • Putting the Brakes on Brachyury: Identifying and Targeting a Conserved Transcriptional Network that Drives Primary and Metastatic Brain Tumor Initiation and Propagation

    Final Number:
    40

    Authors:
    Sagar R. Shah MS; Justin M David PhD; Nathaniel Tippens; Ahmed Mohyeldin MD; Juan Carlos Martinez-Gutierrez; Sara Ganaha MD; Kristen Kozielski; Jordan Green; Andre Levchenko; Claudia Palena PhD; Alfredo Quinones-Hinojosa MD

    Study Design:
    Laboratory Investigation

    Subject Category:
    Tumor Section

    Meeting: 2016 Tumor Section Satellite Symposium

    Introduction: Accumulating evidence suggests malignant neoplasms contain a distinct subset of cells that hijack stem cell transcriptional programs to attain tumor initiating and propagating abilities. As such, transcriptional programs coordinating early embryogenesis have recently emerged as oncogenic drivers and potential therapeutic targets. Brachyury, a core T-box transcription factor, plays a vital role during development. Incidentally, Brachyury is overexpressed in several cancers including primary and metastatic brain tumors where it promotes growth, confers resistance to chemo- and radiotherapy, and drives metastatic potential, resulting in poor patient prognosis. However, the molecular underpinnings of this aggressive and aberrant transcriptional network are not fully understood.

    Methods: Patient-derived chordoma, glioblastoma, metastases to the brain, lung cancer tissues (n>20) and primary and commercial cells were subject to western blotting, qRT-PCR, bioinformatics analyses, in vitro and in vivo experiments (n=10) using genetic and pharmacological inhibitors

    Results: Our studies demonstrate that Brachyury drives cell cycle progression, stemness, and EMT through direct transcriptional activation of the proto-oncogene YAP, an effector of the Hippo pathway and master regulator of organ development, in chordoma (p<0.05). In addition, Brachyury regulates protein stability of YAP in more prevalent and lethal tumors such as glioblastoma (GBM), metastases to the brain, and epithelial-based cancers (p<0.05). Furthermore, we found the Brachyury-YAP signaling forms a negative feedback loop that ensures genetic stability of this aggressive network (p<0.05). Targeting this network, using a proprietary nanoparticle-based genetic inhibitor, attenuates aggressive cancer growth and progression in vitro and in vivo (p<0.05).

    Conclusions: Our work provides new molecular insights into the conserved biology of relatively slow progressing, rare tumors such as chordoma, lethal and highly aggressive cancers such as GBM and metastases to the brain, and even prevalent tumors such as lung cancer. Moreover, our novel nanotechnology-based Brachyury-YAP targeting system offers hope for the management and treatment of a wide range of malignant neoplasms.

    Patient Care: -It will shed light on the biology of rare cancers such as Chordoma -It will highlight the conserved mechanisms shared by aggressive cancers such as GBMs and brain metastases and more prevalent tumors such as lung cancer. -Highlights the importance of understanding this mechanism of aggressive growth and dissemination by identifying potent therapeutic targets -Highlights the use of nanotechnology-based gene therapy for clinical use

    Learning Objectives: -Understand the role of Brachyury-driven transcriptional network in cancer -Understand the role of YAP-dependent Brachyury signaling in rare and prevalent cancer. -Understand the use of novel nanotechnology to target aggressive and aberrant transcriptional networks in cancer

    References:

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