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Twist1-induced invadopodia formation promotes tumor metastasis.

ABSTRACT: The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation. Twist1 induces PDGFR? expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFR? are central mediators of invadopodia formation in response to various EMT-inducing signals. Induction of PDGFR? and invadopodia is essential for Twist1 to promote tumor metastasis. Consistent with PDGFR? being a direct transcriptional target of Twist1, coexpression of Twist1 and PDGFR? predicts poor survival in breast tumor patients. Therefore, invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis.

SUBMITTER: Eckert MA

PROVIDER: S-EPMC3072410 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Twist1-induced invadopodia formation promotes tumor metastasis.

Eckert Mark A MA Lwin Thinzar M TM Chang Andrew T AT Kim Jihoon J Danis Etienne E Ohno-Machado Lucila L Yang Jing J

Cancer cell 20110301 3

The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation in response to various EMT-inducing signals. Induct ...[more]

PMID: 21397860

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Project description:BackgroundMetastatic bladder cancer (BLCA) is a lethal disease with an unmet need for study. Transgelin (TAGLN) is an actin-binding protein that affects the dynamics of the actin cytoskeleton indicating its robust potential as a metastasis initiator. Here, we sought to explore the expression pattern of TAGLN and elucidate its specific functioning and mechanisms in BLCA.MethodsA comprehensive assessment of TAGLN expression in BLCA was performed in three cohorts with a total of 847 patients. The potential effects of TAGLN on BLCA were further determined using clinical genomic analyses that guided the subsequent functional and mechanistic studies. In vitro migration, invasion assays and in vivo metastatic mouse model were performed to explore the biological functions of TAGLN in BLCA cells. Immunofluorescence, western blot and correlation analysis were used to investigate the molecular mechanisms of TAGLN.FindingsTAGLN was highly expressed in BLCA and correlated with advanced prognostic features. TAGLN promoted cell colony formation and cell migration and invasion both in vitro and in vivo by inducing invadopodia formation and epithelial-mesenchymal transition, during which a significant correlation between TAGLN and Slug was observed. The progression-dependent correlation between TGF-β and TAGLN was analysed at both the cellular and tissue levels, while TGF-β-mediated migration was abolished by the suppression of TAGLN.InterpretationOverall, TAGLN is a promising novel prognosis biomarker of BLCA, and its metastatic mechanisms indicate that TAGLN may represent a novel target agent that can be utilized for the clinical management of invasive and metastatic BLCA. FUND: This work was supported by the National Natural Science Foundation of China [81772703, 81672546, 81602253]; the Natural Science Foundation of Beijing [71772219, 7152146]. and Innovative Fund for Doctoral Students of Peking University Health Science Center (BUM2018BSS002). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report.

Dataset Information

Twist1-induced invadopodia formation promotes tumor metastasis.

Publications

Twist1-induced invadopodia formation promotes tumor metastasis.

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