217 YAP Is Ready to Rac and Rho: Elucidation of a Novel YAP-Driven Network That Potentiates Brain Cancer Cell Dispersal and Confers Poor Survival in Patients

Sagar R. Shah, Nathaniel Tippens, Jin Seok Park, Ahmed Mohyeldin, Guillermo Vela, Juan Carlos Martinez-Gutierrez, Seth S. Margolis, Susanne Schmidt, Andre Levchenko, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

INTRODUCTION: Molecular pathways linking cell polarization and migration to extracellular cues regulate many pathological processes, including progression of aggressive and infiltrative cancers. Glioblastoma (GBM), the most common and lethal form of primary brain cancer, is characterized by its pronounced ability to disseminate into the intricate microenvironment of the human brain, confounding surgical excision and radiotherapy, leading to a median patient survival of 14 months. Progression results from defects in molecular pathways linking cell migration and invasion into surrounding tissue. However, the molecular engines are not known.

METHODS: Using patient-derived GBM tissues and cells, we profiled the expression of network moieties via Western blotting, quantitative real-time polymerase chain reaction and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a prodispersal mechanism for management and treatment of GBMs.

RESULTS: Yes-associated protein (YAP), a transcriptional coactivator, is overexpressed and hyperactive in 78% of GBMs and 50% of metastatic tumors to the brain (P < .05). Our studies demonstrate that YAP activates a Rho-GTPase switch to potentiate migratory speed by interacting with canonical pathways through direct transcriptional control. In addition, YAP mediates a proinvasive genetic network by direct posttranslational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (P < .05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and The Cancer Genome Atlas (P < .05), suggesting a new signature in clinical prognosis of this aggressive and infiltrative cancer. Targeting this network using a proprietary pharmacological inhibitor attenuates tumor dispersal and growth (P < .05).

CONCLUSION: YAP can critically control cellular locomotion through direct interaction with canonical molecular pathways controlling invasion and migration. Understanding the molecular underpinnings of this network is vital to the development of imperative prognostic and treatment approaches for cancer such as the new proprietary pharmacological inhibitor presented in this study.

Original languageEnglish (US)
Number of pages1
JournalNeurosurgery
Volume63
DOIs
StatePublished - Aug 1 2016

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Brain Neoplasms
Glioblastoma
Survival
Neoplasms
Proteins
Pharmacology
Cell Movement
rho GTP-Binding Proteins
Aptitude
Atlases
Pathologic Processes
Locomotion
Computational Biology
Cues
Real-Time Polymerase Chain Reaction
Microscopy
Radiotherapy
Western Blotting
Genome
Biopsy

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

217 YAP Is Ready to Rac and Rho : Elucidation of a Novel YAP-Driven Network That Potentiates Brain Cancer Cell Dispersal and Confers Poor Survival in Patients. / Shah, Sagar R.; Tippens, Nathaniel; Park, Jin Seok; Mohyeldin, Ahmed; Vela, Guillermo; Martinez-Gutierrez, Juan Carlos; Margolis, Seth S.; Schmidt, Susanne; Levchenko, Andre; Quinones-Hinojosa, Alfredo.

In: Neurosurgery, Vol. 63, 01.08.2016.

Research output: Contribution to journalArticle

Shah, Sagar R. ; Tippens, Nathaniel ; Park, Jin Seok ; Mohyeldin, Ahmed ; Vela, Guillermo ; Martinez-Gutierrez, Juan Carlos ; Margolis, Seth S. ; Schmidt, Susanne ; Levchenko, Andre ; Quinones-Hinojosa, Alfredo. / 217 YAP Is Ready to Rac and Rho : Elucidation of a Novel YAP-Driven Network That Potentiates Brain Cancer Cell Dispersal and Confers Poor Survival in Patients. In: Neurosurgery. 2016 ; Vol. 63.
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abstract = "INTRODUCTION: Molecular pathways linking cell polarization and migration to extracellular cues regulate many pathological processes, including progression of aggressive and infiltrative cancers. Glioblastoma (GBM), the most common and lethal form of primary brain cancer, is characterized by its pronounced ability to disseminate into the intricate microenvironment of the human brain, confounding surgical excision and radiotherapy, leading to a median patient survival of 14 months. Progression results from defects in molecular pathways linking cell migration and invasion into surrounding tissue. However, the molecular engines are not known.METHODS: Using patient-derived GBM tissues and cells, we profiled the expression of network moieties via Western blotting, quantitative real-time polymerase chain reaction and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a prodispersal mechanism for management and treatment of GBMs.RESULTS: Yes-associated protein (YAP), a transcriptional coactivator, is overexpressed and hyperactive in 78{\%} of GBMs and 50{\%} of metastatic tumors to the brain (P < .05). Our studies demonstrate that YAP activates a Rho-GTPase switch to potentiate migratory speed by interacting with canonical pathways through direct transcriptional control. In addition, YAP mediates a proinvasive genetic network by direct posttranslational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (P < .05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and The Cancer Genome Atlas (P < .05), suggesting a new signature in clinical prognosis of this aggressive and infiltrative cancer. Targeting this network using a proprietary pharmacological inhibitor attenuates tumor dispersal and growth (P < .05).CONCLUSION: YAP can critically control cellular locomotion through direct interaction with canonical molecular pathways controlling invasion and migration. Understanding the molecular underpinnings of this network is vital to the development of imperative prognostic and treatment approaches for cancer such as the new proprietary pharmacological inhibitor presented in this study.",
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T2 - Elucidation of a Novel YAP-Driven Network That Potentiates Brain Cancer Cell Dispersal and Confers Poor Survival in Patients

AU - Shah, Sagar R.

AU - Tippens, Nathaniel

AU - Park, Jin Seok

AU - Mohyeldin, Ahmed

AU - Vela, Guillermo

AU - Martinez-Gutierrez, Juan Carlos

AU - Margolis, Seth S.

AU - Schmidt, Susanne

AU - Levchenko, Andre

AU - Quinones-Hinojosa, Alfredo

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N2 - INTRODUCTION: Molecular pathways linking cell polarization and migration to extracellular cues regulate many pathological processes, including progression of aggressive and infiltrative cancers. Glioblastoma (GBM), the most common and lethal form of primary brain cancer, is characterized by its pronounced ability to disseminate into the intricate microenvironment of the human brain, confounding surgical excision and radiotherapy, leading to a median patient survival of 14 months. Progression results from defects in molecular pathways linking cell migration and invasion into surrounding tissue. However, the molecular engines are not known.METHODS: Using patient-derived GBM tissues and cells, we profiled the expression of network moieties via Western blotting, quantitative real-time polymerase chain reaction and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a prodispersal mechanism for management and treatment of GBMs.RESULTS: Yes-associated protein (YAP), a transcriptional coactivator, is overexpressed and hyperactive in 78% of GBMs and 50% of metastatic tumors to the brain (P < .05). Our studies demonstrate that YAP activates a Rho-GTPase switch to potentiate migratory speed by interacting with canonical pathways through direct transcriptional control. In addition, YAP mediates a proinvasive genetic network by direct posttranslational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (P < .05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and The Cancer Genome Atlas (P < .05), suggesting a new signature in clinical prognosis of this aggressive and infiltrative cancer. Targeting this network using a proprietary pharmacological inhibitor attenuates tumor dispersal and growth (P < .05).CONCLUSION: YAP can critically control cellular locomotion through direct interaction with canonical molecular pathways controlling invasion and migration. Understanding the molecular underpinnings of this network is vital to the development of imperative prognostic and treatment approaches for cancer such as the new proprietary pharmacological inhibitor presented in this study.

AB - INTRODUCTION: Molecular pathways linking cell polarization and migration to extracellular cues regulate many pathological processes, including progression of aggressive and infiltrative cancers. Glioblastoma (GBM), the most common and lethal form of primary brain cancer, is characterized by its pronounced ability to disseminate into the intricate microenvironment of the human brain, confounding surgical excision and radiotherapy, leading to a median patient survival of 14 months. Progression results from defects in molecular pathways linking cell migration and invasion into surrounding tissue. However, the molecular engines are not known.METHODS: Using patient-derived GBM tissues and cells, we profiled the expression of network moieties via Western blotting, quantitative real-time polymerase chain reaction and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a prodispersal mechanism for management and treatment of GBMs.RESULTS: Yes-associated protein (YAP), a transcriptional coactivator, is overexpressed and hyperactive in 78% of GBMs and 50% of metastatic tumors to the brain (P < .05). Our studies demonstrate that YAP activates a Rho-GTPase switch to potentiate migratory speed by interacting with canonical pathways through direct transcriptional control. In addition, YAP mediates a proinvasive genetic network by direct posttranslational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (P < .05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and The Cancer Genome Atlas (P < .05), suggesting a new signature in clinical prognosis of this aggressive and infiltrative cancer. Targeting this network using a proprietary pharmacological inhibitor attenuates tumor dispersal and growth (P < .05).CONCLUSION: YAP can critically control cellular locomotion through direct interaction with canonical molecular pathways controlling invasion and migration. Understanding the molecular underpinnings of this network is vital to the development of imperative prognostic and treatment approaches for cancer such as the new proprietary pharmacological inhibitor presented in this study.

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