Abstract
Abstract Intravital imaging of rodent mammary tumors has shown that direct contacts between a Mena expressing tumor cell, a perivascular macrophage and an endothelial cell forms a microanatomical structure named TMEM (Tumor Microenvironment of Metastasis). Clinical studies have shown that the number of TMEM is correlated with an increased risk of developing distant metastasis in breast cancer patients. While TMEM is an excellent prognostic marker for predicting metastasis the mechanisms of TMEM assembly and function are not understood. Recently, we showed that heterotypic cell contact between tumor cells and macrophages induces the formation of invadopodia in tumor cells, invasive structures necessary for matrix degradation and required for tumor cell intravasation. Using high resolution FRET imaging, we further found that macrophage-induced invadopodium formation is dependent on RhoA activation in the tumor cell. However, what remained to be determined was the signaling pathway that regulated this heterotypic cell contact-mediated phenomenon. We explored the role of NOTCH, a known receptor involved in heterotypic cell contact signaling, in stimulating macrophage-dependent tumor cell invadopodium formation and transendothelial migration. We found that, in the absence of Notch signaling, macrophage-induced invadopodium formation and tumor cell intravasation are abolished. Moreover, RhoA is no longer activated in tumor cells upon macrophage contact when Notch signaling is perturbed. These results show that Notch signaling regulates heterotypic cell contact mediated invadopodium formation through RhoA activation, and reveals a novel non-canonical NOTCH/RhoA pathway as a molecular target to prevent TMEM function and therefore metastasis. Citation Format: Jose Javier Bravo Cordero, Minna Roh-Johnson, Jeanine Pignatelli, Maja Oktay, Louis Hodgson, John Condeelis. Macrophage-dependent activation of a non-canonical NOTCH-RhoA signaling pathway regulates tumor cell intravasation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4034. doi:10.1158/1538-7445.AM2015-4034
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call