Glioblastomas (GBM) are the most malignant and common intrinsic brain tumor. Despite aggressive treatment the disease is uniformly fatal and patients survive on average less than a year. Our inability to improve disease outcome is due in large part to gaps in our understanding of what mechanisms activate GBM invasion. We first identified the role of TWIST1 in GBM invasion and its high correlation with human GBM malignancy. Its critical function in carcinoma invasion and metastasis by activation of epithelial mesenchymal transition (EMT) suggested that it may function through similar mechanisms to promote GBM invasion. Here we present novel data demonstrating the potential role of the secreted matrix protein POSTN, Akt activation and TWIST1 binding protein interactions in TWIST1 pro-invasive signaling in GBM. We hypothesize that a TWIST1 regulatory mechanism signaling through POSTN and specific Akt isoforms that is in turn regulated by TWIST1 binding partners promotes GBM invasion and malignancy. To address this hypothesis and show the therapeutic potential of targeting this TWIST1 signaling network we will i) determine how inhibition of TWIST1 in human GBM stem cells and in a cre/lox conditional TWIST model influences tumor invasion and malignancy in vivo, ii) define the impact of inhibiting POSTN and specific Akt isoforms to abrogate TWIST1 pro-invasive signaling in vivo, and iii) identify TWIST1 binding partners that regulate TWIST1 invasion in concert with regulation of POSTN and Akt. By demonstrating the importance of this network for GBM invasion we will further validate the relevance of EMT mechanisms in non-epithelial derived cancers. As such, these studies are expected to revolutionize concepts of GBM invasion and accelerate generation of sorely needed therapies that target the most lethal biological feature of these dreaded cancers.

Public Health Relevance

The lack of significant improvement in treatment outcomes for patients with glioblastoma (GBM) for over 30 years is due largely to our failure to address the problem of GBM cell invasion into the brain. TWIST1 is a putative oncogene which promotes carcinoma invasion and metastasis through activation of epithelial mesenchymal transition (EMT). We have now confirmed TWIST1 as a critical mediator of GBM invasion and malignancy and here will establish for the first time the therapeutic relevance of a TWIST1 signaling network through POSTN and Akt, in turn regulated by TWIST1 binding partners. By demonstrating the impact of this novel pro-invasive network in GBM invasion we will validate the importance of EMT related mechanisms for GBM, also expected to have great relevance for a much larger group of invasive carcinomas. This paradigm shift is expected to revolutionize our understanding of invasion in GBM, accelerate discovery of therapeutic targets, and translate into significant improvements in GBM patient outcomes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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University of Washington
Schools of Medicine
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Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202
Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy et al. (2018) An anatomic transcriptional atlas of human glioblastoma. Science 360:660-663
Mikheev, Andrei M; Mikheeva, Svetlana A; Tokita, Mari et al. (2017) Twist1 mediated regulation of glioma tumorigenicity is dependent on mode of mouse neural progenitor transformation. Oncotarget 8:107716-107729
Mikheev, Andrei M; Mikheeva, Svetlana A; Trister, Andrew D et al. (2015) Periostin is a novel therapeutic target that predicts and regulates glioma malignancy. Neuro Oncol 17:372-82
Kumar, Akash; Boyle, Evan A; Tokita, Mari et al. (2014) Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes. Genome Biol 15:530
Chang, Tim C; Mikheev, Andrei M; Huynh, Wilson et al. (2014) Parallel microfluidic chemosensitivity testing on individual slice cultures. Lab Chip 14:4540-51
Ramakrishna, Rohan; Rostomily, Robert (2013) Seed, soil, and beyond: The basic biology of brain metastasis. Surg Neurol Int 4:S256-64
Stoll, Elizabeth A; Horner, Philip J; Rostomily, Robert C (2013) The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment. Aging Cell 12:733-41
Mikheev, Andrei M; Ramakrishna, Rohan; Stoll, Elizabeth A et al. (2012) Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy. Aging Cell 11:1027-35
Mikheev, Andrei M; Stoll, Elizabeth A; Ramakrishna, Rohan et al. (2012) Geropotency: increased malignant potential of aging neural progenitors. Aging (Albany NY) 4:854-5

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