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| Invited Talk, Friday, 09:00 – 09:30 |
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| Amplification of signaling
pathways to actin polymerization and chemotaxis in breast tumor cells in
vivo
John S. Condeelis
Gruss Lipper Biophotonics Center,
Albert Einstein College of Medicine of Yeshiva University, New York, USA |
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| Contact:
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Multi-photon microscopy (MPM) allows the observation of tumor cell behavior
in mammary tumors and has demonstrated that invasive carcinoma cells form
migratory streams and intravasate only when associated with macrophages.
The in vivo invasion assay was developed to collect these tumor cells during
migration toward and intravasation into blood vessels. The in vivo invasion
assay was coupled to expression profiling to reveal the genes expressed
by tumor cells during migration and intravasation in rat, mouse and human
breast tumors. This expression profile is called the Invasion Signature.
The motility pathways identified in the Invasion Signature converge
on the Cofilin/Mena pathway identifying it as a master regulator of chemotaxis,
invasion and dissemination of breast tumor cells in vivo. Using markers
derived from the Cofilin/Mena pathway, anatomical landmarks have been developed
for use with breast cancer patients. One of these, composed of an invading
carcinoma cell marked by Mena over-expression, and a peri-vascular macrophage,
is called TMEM (Tumor MicroEnvironment for Metastasis) in human breast
tumors. Another is cofilin x P-cofilin, a marker of activation of the Cofilin/Mena
pathway in tumor cells. TMEM density and cofilin x P-cofilin intensity
are each predictors of metastatic risk in human invasive ductal carcinomas
of the breast.
An important clue as to mechanism relating the Cofilin/Mena pathway
to metastasis is the finding that migrating tumor cells in vivo exhibit
alternative splicing of Mena resulting in increased expression of MenaINV
isoform and decreased expression of Mena11a isoform. Furthermore, MenaINV
enhances the sensitivity of EGFR in tumor cells to EGF by 50 fold and increases
paracrine signaling with macrophages while Mena 11a decreases EGF sensitivity
and CSF1 synthesis in tumor cells dramatically decreasing paracrine signaling
with macrophages. The consequences of increased sensitivity of EGFR are
profound resulting in increased tumor cell chemotaxis, streaming migration,
dissemination and metastasis in vivo in mouse mammary tumors.
An underlying molecular mechanism by which MenaINV increases
EGFR sensitivity to EGF is its ability to activate EGFR to stimulate PLCgamma
to activate cofilin. This creates new actin polymerization at the plasma
membrane. Hence, MenaINV results in increased Cofilin-mediated
chemotaxis toward macrophages and macrophage-mediated transendothelial
migration.
| [1] |
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Philippar, Roussos, Oser, Yamaguchi,
Kim, Giampieri, Wang, Goswami, Wyckoff, Lauffenburger, Sahai, Condeelis
and Gertler: A Mena invasion
isoform potentiates EGF-induced carcinoma cell invasion and metastasis,
Developmental Cell 15 (6): 813-28 (2008). |
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| [2] |
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Roussos, Balsamo, Alford, Wyckoff, Gligorijevic,
Wang, Pozzuto, Stobezki, Goswami, Segall, Lauffenburger, Bresnick, Gertler
and Condeelis:
Mena invasive (Mena
INV) promotes multicellular streaming motility and transendothelial migration
in a mouse model breast cancer, J. Cell Science 124: 2120-31
(2011). |
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| [3] |
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Roussos, Condeelis and Patsialou: Chemotaxis
in cancer, Nature Reviews Cancer, in press (2011). |
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