TY - JOUR
T1 - TWIST1 promotes invasion through mesenchymal change in human glioblastoma
AU - Mikheeva, Svetlana A.
AU - Mikheev, Andrei M.
AU - Petit, Audrey
AU - Beyer, Richard
AU - Oxford, Robert G.
AU - Khorasani, Leila
AU - Maxwell, John Patrick
AU - Glackin, Carlotta A.
AU - Wakimoto, Hiroaki
AU - González-Herrero, Inés
AU - Sánchez-García, Isidro
AU - Silber, John R.
AU - Horner, Philip J.
AU - Rostomily, Robert C.
N1 - Funding Information:
We acknowledge Rosemary Kimmel for her expert editorial assistance, J. Barber for the help with statistical analysis, Drs Jing Zhang, Eduardo Mendez and Daniel Silbergeld for critical review of the manuscript, Theo Bammler and Frederico Farin of the UW CHDD Genomics Core for assistance with microarray studies, Glen MacDonald of the CHDD Cellular Morphology Core for assistance with development of whole brain tumor imaging techniques, Drs Daniel L Silbergeld, Alexander M Spence, Jason Rockhill, and Maciej Mrugala whose clinical efforts made this work possible. This research was funded in part through an NIH/NINDS T32-NS-0007144 Clinical Neuroscience Training Grant (RO, LK, JM) and a University of Washington Institutional Bridge Funding Grant (RCR, AKM). Research in ISG group is supported partially by FEDER and by MICINN (SAF2009-08803), Junta de Castilla y León (CSI13A08 and proyecto Biomedicina 2009-2010), MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), Sandra Ibarra Foundation, NIH grant (R01 CA109335-04A1) and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon. There are no conflicts of interest.
PY - 2010/7/20
Y1 - 2010/7/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77954674187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954674187&partnerID=8YFLogxK
U2 - 10.1186/1476-4598-9-194
DO - 10.1186/1476-4598-9-194
M3 - Article
C2 - 20646316
AN - SCOPUS:77954674187
SN - 1476-4598
VL - 9
JO - Molecular Cancer
JF - Molecular Cancer
M1 - 194
ER -