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.
|Leung, E; Xue, A; Wang, Y et al. (2017) Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene 36:2680-2692|
|Eddy, Robert J; Weidmann, Maxwell D; Sharma, Ved P et al. (2017) Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis. Trends Cell Biol 27:595-607|
|Donnelly, Sara K; Cabrera, Ramon; Mao, Serena P H et al. (2017) Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. J Cell Biol 216:4331-4349|
|Rosenberg, Brian J; Gil-Henn, Hava; Mader, Christopher C et al. (2017) Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. Mol Biol Cell 28:1347-1360|
|Jiang, Chang; Ding, Zhijie; Joy, Marion et al. (2017) A balanced level of profilin-1 promotes stemness and tumor-initiating potential of breast cancer cells. Cell Cycle 16:2366-2373|
|Karagiannis, George S; Pastoriza, Jessica M; Wang, Yarong et al. (2017) Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med 9:|
|Harney, Allison S; Karagiannis, George S; Pignatelli, Jeanine et al. (2017) The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors. Mol Cancer Ther 16:2486-2501|
|Oudin, Madeleine J; Hughes, Shannon K; Rohani, Nazanin et al. (2016) Characterization of the expression of the pro-metastatic Mena(INV) isoform during breast tumor progression. Clin Exp Metastasis 33:249-61|
|Balsamo, Michele; Mondal, Chandrani; Carmona, Guillaume et al. (2016) The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior. Sci Rep 6:35298|
|Pignatelli, Jeanine; Bravo-Cordero, Jose Javier; Roh-Johnson, Minna et al. (2016) Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/MenaINV-initiated invadopodium formation. Sci Rep 6:37874|
Showing the most recent 10 out of 46 publications