Twist1-Induced Invadopodia Formation Promotes Tumor Metastasis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Tumor cells acquire the ability to degrade basement membrane and extracellular matrix (ECM), thus allowing them to invade and metastasize to distant organs. The molecular triggers for ECM degradation and invasion are largely unknown. The Twist1 transcription factor plays key roles in tumor metastasis and is known to induce Epithelial-Mesenchymal Transition (EMT). In addition to Twist1, a number of studies show that other EMT-inducing transcription factors, including Snail1/Snail2 and ZEB1/ZEB2, are also important players in tumor metastasis. One question unanswered is what are the specific cellular functions and transcriptional targets of individual EMT-inducing transcription factors required for EMT and tumor metastasis. Here we report a novel function of Twist1 in promoting extracellular matrix degradation by inducing the formation of invadopodia. Invadopodia are specialized actin-based membrane protrusions that degrade ECM via clustering of proteases. Invadopodia contain a F-actin core and actin regulatory proteins, such as cortactin, the unique adaptor proteins Tks4 and Tks5 in clustering components of invadopodia, and a large number of proteases for matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src kinase in various breast tumor cells. Phosphorylation of multiple invadopodia components by Src kinase promotes invadopodia assembly and matrix degradation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation and ECM degradation in response to various EMT-inducing signals, including TGFβ and Snail1. Induction of PDGFRα and invadopodia is essential for Twist1 to promote invadopodia formation, local tumor invasion, and distant metastasis in vivo. Consistent with PDGFRα being a direct transcriptional target of Twist1, expression of Twist1 and PDGFRα is highly correlated and associated with poor survival in breast cancer patients. Together, our study demonstrates that invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis. Furthermore, it reveals that matrix degradation and loss of cell adhesion are regulated by different EMT-inducing transcription factors. This explains why multiple factors need to be activated coordinately to promote carcinoma cells to undergo EMT and invade. We also identify PDGFRα as a direct transcriptional target of Twist1 in promoting invadopodia formation and tumor metastasis, therefore suggesting that PDGFRs might be potential targets for anti-metastasis therapies. Grant acknowledgements: NIH Director's New Innovator Award (DP2 OD002420-01), Kimmel Scholar Award, and California Breast Cancer Research Program(12IB-0065) to J.Y. a DOD Breast Cancer Pre-doctoral fellowship to M.A.E, a DOD Breast Cancer Era of Hope Postdoctoral Fellowship to E.D., Susan G. Komen Foundation grant FAS0703850 to J.K. and L.O. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4747. doi:10.1158/1538-7445.AM2011-4747