An essential step in metastatic dissemination of tumor cells involves intravasation where the carcinoma cell must cross the basement membrane of the duct/acinus and then the basement membrane of the endothelium of blood vessels. The ability to degrade and penetrate the dense extracellular matrix of a basement membrane is important for transmigration in both cases. Degradation and penetration of basement membranes is generally believed to require protrusive activity of tumor cells, in particular, the formation of invadopodia and lamallipodia, which are regulated by EGF receptor and tyrosine kinase signaling. Invadopodia are protrusions of the tumor cell membrane with associated protease activity. The ability to make invadopodia is correlated with metastatic potential in tumor cells. To identify the mechanisms regulating the steps to invadopodium maturation, and thereby understand how invadopodia are involved in both chemotaxis and invasion of tumor cells, during the previous funding period we studied the initiation and maturation of invadopodia in detail. During these studies we identified 4 stages of formation of an invadopodium: precursor formation;activation of actin polymerization;stabilization and ECM degradation. During progression through these stages, key regulatory events were identified including: 1. N-WASp activation dependent recruitment of cortactin;2. the regulation of cofilin activity by binding of cofilin to cortactin;3. Cofilin and N-WASp dependent actin polymerization;4. Arg-dependent cortactin phosphorylation which regulates #s 1-3;5. Rho-family G-protein dependent regulation of N-WASp, cofilin and degradation of ECM. In this application we propose to study each of these regulatory events, and the mechanisms by which they are choreographed, during invadopodium formation and cancer cell migration.

Public Health Relevance

Metastasis is the primary cause of death for cancer patients. Escape from the primary tumor and invasion into a new tissue depends on the ability of cancer cells to migrate. The initial step in breast carcinoma cell invasion involves tumor cells crossing the basement membrane of the mammary duct/acinus. An essential step in metastatic dissemination of tumor cells involves intravasation where the carcinoma cell must again cross the basement membrane of the endothelium of blood vessels. Degradation and penetration of basement membranes is generally believed to require protrusive activity of tumor cells, in particular the formation of invadopodia and lamallipodia. In this application we propose to study the regulation and function of invadopodia in breast tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150344-26
Application #
8607159
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Mohla, Suresh
Project Start
1988-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
26
Fiscal Year
2014
Total Cost
$318,444
Indirect Cost
$126,610
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Moshfegh, Yasmin; Bravo-Cordero, Jose Javier; Miskolci, Veronika et al. (2014) A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. Nat Cell Biol 16:574-86
Roh-Johnson, M; Bravo-Cordero, J J; Patsialou, A et al. (2014) Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene 33:4203-12
Beaty, Brian T; Condeelis, John (2014) Digging a little deeper: the stages of invadopodium formation and maturation. Eur J Cell Biol 93:438-44
Beaty, Brian T; Wang, Yarong; Bravo-Cordero, Jose Javier et al. (2014) Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. J Cell Biol 205:737-51
Kwon, Mijung; Lee, Soo Jin; Wang, Yarong et al. (2014) Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis. Int J Cancer 135:48-60
Bravo-Cordero, Jose Javier; Hodgson, Louis; Condeelis, John S (2014) Spatial regulation of tumor cell protrusions by RhoC. Cell Adh Migr 8:263-7
Sharma, Ved P; Beaty, Brian T; Cox, Dianne et al. (2014) An in vitro one-dimensional assay to study growth factor-regulated tumor cell-macrophage interaction. Methods Mol Biol 1172:115-23
Beaty, Brian T; Sharma, Ved P; Bravo-Cordero, Jose J et al. (2013) ?1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol Biol Cell 24:1661-75, S1-11
Bravo-Cordero, Jose Javier; Moshfegh, Yasmin; Condeelis, John et al. (2013) Live cell imaging of RhoGTPase biosensors in tumor cells. Methods Mol Biol 1046:359-70
Tania, Nessy; Condeelis, John; Edelstein-Keshet, Leah (2013) Modeling the synergy of cofilin and Arp2/3 in lamellipodial protrusive activity. Biophys J 105:1946-55

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