Cell Migration and Tumor Progression
Our lab investigates projects related to cell migration and tumor progression, including:
- The role of p120 in migration and invasiveness
- Receptor tyrosine kinase signaling
- p120 and cell transformation
The role of p120 in migration and invasiveness
A primary research focus led by Dr. Anastasiadis is to elucidate the role of cadherins and catenins in regulating cell migration and promoting invasion and metastasis (for a review, see Anastasiadis and Reynolds, Curr Opin Cell Biol, 2001). In particular, we're investigating E-cadherin-mediated signaling events that suppress cell motility and invasiveness and promote the reorganization of the actin cytoskeleton.
Our preliminary data indicate that endogenous p120 promotes the motility and invasiveness of E-cadherin-deficient cells. Association of cytoplasmic p120 in these cells with ectopically expressed E-cadherin blocks the p120 pro-migratory effects and provides a potential explanation for E-cadherin-mediated suppression of invasiveness.
Current studies on this project are focused on:
- Testing the hypothesis that p120 binding mediates the pro-migratory, prometastatic functions of mesenchymal cadherins
- Elucidating the role of Rho GTPases in p120-induced motility and invasiveness
- Validating cell culture data in animal models of tumor invasion and metastasis
- Mapping of p120 domains that mediate increased motility and invasiveness
- Using proteomics to identify p120 binding partners involved in motility and invasiveness
- Following up on microarray data supporting the involvement of particular signaling pathways in the p120 effects
- Determining the role of p120 isoform expression and phosphorylation status in adhesion and invasiveness
Receptor tyrosine kinase signaling
Receptor tyrosine kinases (RTKs) are often overactivated in human cancer. Their activation induces signaling cascades that control cell growth, survival and cell motility. We postulate that intact E-cadherin complexes actively repress RTK pro-migratory functions, while dissolution of cadherin complexes or loss of E-cadherin expression during tumor progression relieves this repression.
Several studies suggest that preserving E-cadherin function prevents invasiveness. We are testing the hypothesis that the association of E-cadherin complexes with RTKs is required for cadherin-mediated induction of Rho GTPases, maturation of cell junctions and suppression of invasiveness.
Given recent evidence that β-catenin and p120 mediate the pro-migratory functions of RTKs, we postulate that small cadherin-catenin fragments could be identified that block the dissolution of junctions after sustained activation of RTKs, thereby preventing invasiveness. Our preliminary data indicate that overexpression of such fragments blocks the invasiveness of MDA-MB-231 breast cancer cells in vitro. We're also testing the efficacy of these fragments in preventing invasiveness and metastasis in nude mice, using whole-animal imaging techniques that allow the visualization of tumor growth and metastasis in live animals.
Finally, we're investigating the mechanism by which p120 mediates HGF/c-Met signaling, and we're testing the hypothesis that p120 is also required for signaling downstream of other RTKs, including Her2.
p120 and cell transformation
While β-catenin signaling is known to affect cell growth, little is known about p120's effects on tumor growth, cell transformation, apoptosis or chemosensitivity.
One of our projects is focused on elucidating p120's effects on tumor growth and Ras-mediated cell transformation. The mechanism by which p120 affects these processes and the potential involvement of Rho GTPases also are under investigation.
Finally, we're also investigating the involvement of the p120-binding transcription factor Kaiso, because recent data indicate that p120-uncoupled Kaiso can repress classical β-catenin signaling targets, including c-myc and cyclin D1.