Abstract 2013: NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis

The scaffolding protein NEDD9 is an established pro-metastatic marker in several cancers. Nevertheless, the molecular mechanisms of NEDD9 driven metastasis in cancers remain ill defined. Here, using a comprehensive breast cancer (BCa) tissue microarray, we show that increased levels of NEDD9 protein significantly correlated with the transition from carcinoma in situ to invasive carcinoma. NEDD9 expression is crucial for the mesenchymal invasion of cancer cells at the primary site but not at the metastatic site. Depletion of NEDD9 is sufficient to suppress invasion, leading to decrease in circulating tumor cells (CTCs) and lung metastases in xenograft models. Mechanistically, NEDD9 localizes to invasive pseudopods and is required for local matrix degradation via regulation of MMP14 trafficking. Depletion of NEDD9 impaired invasion of cancer cells through inactivation of MMP14 by excess TIMP2 on the cell surface. Re-expression of NEDD9 is sufficient to restore the activity of MMP14 and the invasive properties of BCa cells. Collectively, these findings uncover critical steps in invasion of BCa cells with potential strategy to target metastasis through manipulation of NEDD9. Citation Format: Elena N. Pugacheva, Sarah McLaughlin, Ryan Ice, Anuradha Rajulapati, Polina Kozyulina, Ryan Livengood, Varvara Kozyreva, Yuriy Loskutov, Alexey Ivanov, Scott Weed. NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2013. doi:10.1158/1538-7445.AM2014-2013