Metastasis is the primary cause of death for cancer patients. Dissemination from the primary tumor depends on the ability of cancer cells to migrate. We and others have used multi-photon microscopy to observe the behavior of tumor cells in tumors of living mice in real time. This has demonstrated the presence of streaming migration in mammary tumors. Streaming migration of tumor cells toward blood vessels accumulates tumor cells in the perivascular microenvironment. An essential step in metastatic dissemination of perivascular tumor cells involves intravasation where the tumor cell must cross the basement membrane of the endothelium of blood vessels. Degradation and penetration of the basement membrane requires protrusive invadopodia which are regulated by EGF receptor, alpha5beta1 and its associated Src-regulated Abl-family kinase Arg. Intravasation in vivo requires the assembly and maturation of an invadopodium on the tumor cell that is associated with the blood vessel endothelium. The site in the mammary tumor where this assembly occurs is called TMEM. Invadopodium assembly in TMEM requires activation of Cofilin severin- and cortactin/N-WASP-Arp2/3 complex-mediated actin polymerization. The Mena/RhoC/cofilin pathway of the Invasion Signature activates these proteins to cause localized actin polymerization from the invadopodium core. The activity status of the cofilin pathway, cortactin expression and its phosphorylation and Mena expression in breast tumors are correlated with increased metastatic potential, further implicating these pathways of the Invasion Signature in invadopodium formation, and the metastatic phenotype. In particular, the expression status of Mena isoforms that support TMEM assembly and function, as well as a marker of cofilin activity in situ, independently predict risk of death due to metastasis in breast cancer patients. In addition, the density of TMEM sites in breast tumors predicts risk of distant metastasis in breast cancer patients. These clinical results emphasize the importance of understanding the molecular mechanisms regulating invadopodium assembly and function during chemotaxis of streaming tumor cells toward blood vessels and in TMEM-associated tumor cells. Molecular understanding will not only improve on the 3 existing prognostics resulting from this work (MenaCalc, TMEM and Cofilin) but will also provide pharmaco-dynamic end points as companion diagnostics for drugs designed to inhibit blood vessel-mediated tumor cell dissemination and metastasis.
Clinical results emphasize the importance of understanding the molecular mechanisms regulating invadopodium assembly and function during chemotaxis of streaming tumor cells toward blood vessels and during dissemination of tumor cells to distant sites during metastasis. Molecular understanding of invadopodium assembly will not only improve on the use of existing prognostics but will also provide pharmaco-dynamic end points as companion diagnostics for drugs designed to inhibit blood vessel-mediated tumor cell dissemination and metastasis. During the previous funding period we have made significant progress on dissection of the molecular pathways involved in invadopodium initiation and function. The proposed specific aims will capitalize on these results and extend them to definitive tests of mechanism.
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