Robert Rostomily, MD is an Associate Professor of Neurological Surgery, and has an active neurosurgical practice focusing on skull base tumors. His research focuses on genetic abnormalities in gliomas, using both animal models and human tissue. He has collaborative projects with Dr. Phillip Horner. His research is supported by a National Institutes of Health (NIH) grant.
TWIST1 promotes invasion through mesenchymal change in human glioblastoma.
Background: Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. Dr. Rostomily previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line in vitro.
Results: To further define TWIST1 functions in GBM, Dr. Rostomily tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. The study found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates.
Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified in vitro was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion in vitro and growth of GBM stem cells.
Conclusions: Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change.
Bibliography of Selected Publications
- Rostomily RC, Born DE, Beyer RP, Jin J, Alvord EC, Mikheev AM, et al. Quantitative proteomic analysis of oligodendrogliomas with and without 1p/19q deletion. Journal of proteome research. 2010 May;9(5):2610-8
- Mikheev AM, Stoll EA, Mikheeva SA, Maxwell JP, Jankowski PP, Ray S, et al. A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy. Aging cell. 2009 Aug;8(4):499-501.
- Rhee W, Ray S, Yokoo H, Hoane ME, Lee CC, Mikheev AM, et al. Quantitative analysis of mitotic Olig2 cells in adult human brain and gliomas: Implications for glioma histogenesis and biology. Glia. 2009 Apr;57(5):510-23.
- Spence AM, Muzi M, Swanson KR, O'Sullivan F, Rockhill JK,Rajendran JG, et al. Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 May;14(9):2623
- Swanson KR, Rostomily RC, Alvord EC. A mathematical modelling tool for predicting survival of individual patients following resection of glioblastoma: a proof of principle. British journal of cancer. 2008 Jan;98(1):113-9.
- Rostomily RC, Elias M, Deng M, Elias P, Born DE, Muballe D, et al. Clinical utility of somatostatin receptor scintigraphic imaging (octreoscan) in esthesioneuroblastoma: a case study and survey of somatostatin receptor subtype expression. Head & neck. 2006 Apr;28(4):305-12.
- Douglas JG, Stelzer KJ, Mankoff DA, Tralins KS, Krohn KA, Muzi M, et al. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure. International journal of radiation oncology, biology, physics. 2006 Mar;64(3):886-91.
- Elias MC, Tozer KR, Silber JR, Mikheeva S, Deng M, Morrison RS, et al. TWIST is expressed in human gliomas and promotes invasion. Neoplasia (New York, N.Y.). 2005 Sep;7(9):824-37.
- Bobola MS, Emond MJ, Blank A, Meade EH, Kolstoe DD, Berger MS, et al. Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Dec;10(23):7875-83.
- Spence AM, Peterson RA, Scharnhorst JD, Silbergeld DL,Rostomily RC. Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas. Journal of neuro-oncology. 2004 Oct;70(1):91-5.
- Mesiwala AH, Scampavia LD, Rabinovitch PS, Ruzicka J,Rostomily RC. On-line flow cytometry for real-time surgical guidance. Neurosurgery. 2004 Sep;55(3):551-60; discussion 560-1.
- Vilela MD Rostomily RC. Temporomandibular joint-preserving preauricular subtemporal-infratemporal fossa approach: surgical technique and clinical application. Neurosurgery. 2004 Jul;55(1):143-53; discussion 153-4.
Phone: (206) 543-3570
Fax: (206) 543-8315
University of Washington Medical Center
Department of Neurological Surgery
1959 NE Pacific, Box 356470
Seattle, Washington 98195-6470
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Samuel Browd, MD, PhD
Dr. Browd specializes in pediatric neurosurgery, specifically with children who have hydrocephalus, brain & spinal cord tumors, pediatric cervical spine, spina bifida, chiari malformations, and spacticity.
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