) One of the most foreboding aspects of cancer is its spread, or metastasis, to different tissues throughout the body. This greatly complicates its treatment which might otherwise be cured by surgery. Metastasis occurs when cells break away from the primary tumor, invade adjacent tissues in order to enter the blood stream, later escape from the blood stream (extravasion) and implant into unaffected tissues to seed new tumors. The process of invasion, extravasion and implantation depend on the cells ability to move across and through different tissues. It is essential to understand how cell movements are controlled if we are to develop strategies to prevent and treat cancer metastasis. It is difficult to directly study cell movement in metastasizing tumors in situ. To circumvent this difficulty yet examine cell movements within tissues, the research outlined in this proposal is aimed at understanding how cell movements are controlled using a model system, embryos of the frog, Xenopus laevis, in which cells normally undergo different types of movement in a tissue environment. We have shown that in Xenopus embryos inhibition of PDGF signaling prevents mesoderm cell movement (1). When PDGF binds to its receptor (PDGFR) autophosphorylation of specific tyrosine residues in the receptors intracellular domain generates high affinity binding sites for signaling molecules including RasGAP, Shp-2, c-Src, P13K and PLCy (2).
Three Specific aims are proposed to dissect PDGP signaling in mesoderm cell movement.
Aim 1 : PDGFRs, designed to selectively bind specific signaling molecules, will be used to identify which signaling molecules regulate the movement of cultured mesoderm cells. Time-lapse micrography, confocal microscopy and Boyden chamber assays will be used to monitor cell movement, cell morphology and chemotaxis.
Aim 2 : Once key signaling molecules have been identified in vitro, we will address how these molecules regulate cell movement within the embryo where additional signals from cell adhesion molecules, matrix components and growth factors may modulate PDGP-signaling events.
Aim 3 : PDGF through P13K causes mesoderm cells to spread and undergo rearrangements of the actin cytoskeleton on a fibronectin matrix (3). In other cell types, PDGF signaling through P13K is known to elicit rearrangements of the actin cytoskeleton through Rho small GTP-binding proteins (4). We will determine the role of Rho small GTP-binding proteins in mesoderm cell movement. The cells response to constitutively active or dominant versions of these proteins will be analyzed by time-lapse micrography and confocal microscopy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087375-04
Application #
6607663
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (M1))
Program Officer
Ault, Grace S
Project Start
2000-07-07
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$256,725
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Liu, Kun-Wei; Feng, Haizhong; Bachoo, Robert et al. (2011) SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. J Clin Invest 121:905-17
Symes, Karen; Smith, Erin M; Mitsi, Maria et al. (2010) Sweet cues: How heparan sulfate modification of fibronectin enables growth factor guided migration of embryonic cells. Cell Adh Migr 4:507-10
Wu, Hao; Symes, Karen; Seldin, David C et al. (2009) Threonine 393 of beta-catenin regulates interaction with Axin. J Cell Biochem 108:52-63
Smith, Erin M; Mitsi, Maria; Nugent, Matthew A et al. (2009) PDGF-A interactions with fibronectin reveal a critical role for heparan sulfate in directed cell migration during Xenopus gastrulation. Proc Natl Acad Sci U S A 106:21683-8
Dominguez, I; Sonenshein, G E; Seldin, D C (2009) Protein kinase CK2 in health and disease: CK2 and its role in Wnt and NF-kappaB signaling: linking development and cancer. Cell Mol Life Sci 66:1850-7
Malikova, Marina A; Van Stry, Melanie; Symes, Karen (2007) Apoptosis regulates notochord development in Xenopus. Dev Biol 311:434-48
Ren, Ruiyi; Nagel, Martina; Tahinci, Emilios et al. (2006) Migrating anterior mesoderm cells and intercalating trunk mesoderm cells have distinct responses to Rho and Rac during Xenopus gastrulation. Dev Dyn 235:1090-9
Dominguez, Isabel; Mizuno, Junko; Wu, Hao et al. (2005) A role for CK2alpha/beta in Xenopus early embryonic development. Mol Cell Biochem 274:125-31
Van Stry, Melanie; Kazlauskas, Andrius; Schreiber, Stuart L et al. (2005) Distinct effectors of platelet-derived growth factor receptor-alpha signaling are required for cell survival during embryogenesis. Proc Natl Acad Sci U S A 102:8233-8
Dominguez, Isabel; Mizuno, Junko; Wu, Hao et al. (2004) Protein kinase CK2 is required for dorsal axis formation in Xenopus embryos. Dev Biol 274:110-24

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