This project seeks to develop an experimental system for discovery of cellular factors relevant to metastasis through the use of novel screens for bacteriophage display libraries. High complexity peptide display libraries will be partitioned through differential selection over cell lines exhibiting metastatic behavior as well as over tissues from metastatic human tumors. Such a protein-based affinity selection approach offers two significant advantages over nucleic acid based methodologies: 1) the full spectrum of the cellular phenotype is sampled, including post translational processing and modification; and 2) all molecular surfaces in the cell are sampled simultaneously in a differential selection process, thereby enabling the metastasis-relevant subset of molecular surfaces to emerge above the background of prevalent but irrelevant cellular surfaces. This project proceeds through a series of straightforward proof of principle experiments, beginning with cell-based protein aptamer selections using a rat mammary carcinoma cell line and its metastatic variant. This cell line is also estrogen-dependent, enabling the use of existing estrogen-receptor-specific fusion phage as positive controls for methodology development. Next, the cell lines will be grafted into an animal model system to enable adaptation of the differential selection methods to the natural context of tumor tissue. Finally, the methodologies will be applied to differential selection of peptide aptamers over metastatic human breast cancer tissue. This project will yield a generalizable method for development of specific probes for molecules governing the malignant behavior of any cancer. An additional outcome will be a defined set of probes that will enable in subsequent studies the detailed characterization of molecules relevant to breast cancer metastasis in the animal model system and in human disease.
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| Kenan, Daniel J; Walsh, Elisabeth B; Meyers, Steven R et al. (2006) Peptide-PEG amphiphiles as cytophobic coatings for mammalian and bacterial cells. Chem Biol 13:695-700 |
| Kenan, Daniel J; Strittmatter, Warren J; Burke, James R (2006) Phage display screening for peptides that inhibit polyglutamine aggregation. Methods Enzymol 413:253-73 |
