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Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

TWIST1 promotes invasion through mesenchymal change in human glioblastoma

Authors: Svetlana A Mikheeva, Andrei M Mikheev, Audrey Petit, Richard Beyer, Robert G Oxford, Leila Khorasani, John-Patrick Maxwell, Carlotta A Glackin, Hiroaki Wakimoto, Inés González-Herrero, Isidro Sánchez-García, John R Silber, Philip J Horner, Robert C Rostomily

Published in: Molecular Cancer | Issue 1/2010

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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.
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Metadata
Title
TWIST1 promotes invasion through mesenchymal change in human glioblastoma
Authors
Svetlana A Mikheeva
Andrei M Mikheev
Audrey Petit
Richard Beyer
Robert G Oxford
Leila Khorasani
John-Patrick Maxwell
Carlotta A Glackin
Hiroaki Wakimoto
Inés González-Herrero
Isidro Sánchez-García
John R Silber
Philip J Horner
Robert C Rostomily
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-194

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