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Open Access Highly Accessed Research

TWIST1 promotes invasion through mesenchymal change in human glioblastoma

Svetlana A Mikheeva13, Andrei M Mikheev137, Audrey Petit13, Richard Beyer2, Robert G Oxford1, Leila Khorasani1, John-Patrick Maxwell1, Carlotta A Glackin4, Hiroaki Wakimoto5, Inés González-Herrero6, Isidro Sánchez-García6, John R Silber1, Philip J Horner13 and Robert C Rostomily13*

Author Affiliations

1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle WA, 98195, USA

2 Environmental Health Sciences, University of Washington School of Medicine, Seattle WA, 98195, USA

3 Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle WA, 98195 USA

4 Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte CA, 91010, USA

5 Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston MA, 02114 USA

6 Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC/Universidad de Salamanca, Campus Unamuno, 37007-Salamanca, Spain

7 Petrov Research Institute of Oncology, St.-Petersburg, 197758, Russia

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Molecular Cancer 2010, 9:194  doi:10.1186/1476-4598-9-194

Published: 20 July 2010

Abstract

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. We 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 we tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. We 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.