Of the many types of cancers facing diagnosis and treatment, malignant melanoma and breast carcinoma have been increasing at an alarming rate in the United States over the past two decades. Classically, diagnosis of melanoma has relied on the presence of several protein markers, including vimentin; whereas, breast carcinoma generally expresses cytokeratin proteins. Vimentin and cytokeratins are both IFs, which are considered principal components of the cytoskeleton of mammalian cells. Although earlier studies emphasized the use of IFs as cell type-specific markers in differentiation and pathology, recent reports have confounded nonepithelial neoplasms. The long range goal of this project remains """"""""the elucidation of key mechanisms responsible for tumor cell invasion and metastasis"""""""". More specifically, this application focuses on achieving a better understanding of the dedifferentiated, interconverted tumor cell phenotype which coexpresses both simple epithelial keratins 8+18 and vimentin IFs, and is associated with increased invasive and metastatic activity, in both human melanoma and breast carcinoma. The following Specific Aims have been designed to address the basic question """"""""which biological properties have been altered in cells which coexpress vimentin and keratins 8+18 IFs that result in increased invasiveness?"""""""".
Specific Aim 1 : Measure interactions of interconverted cells (from melanoma and breast carcinoma models) with simple mesenchymal and epithelial matrices (versus complex matrices, with respect to determining which ECMs facilitate tumor cell adhesion, directed motility and invasiveness via integrin signaling.
Specific Aim 2 : Elucidate the reorganization of key cytoskeletal components in response to cellular interactions with inductive ECMs via integrin-signaling.
Specific Aim 3 : Test the validity of key in vitro observations, generated from Specific Aims 1 and 2 in the SCID mouse model, including the introduction of tumor cells with their respective inductive ECMs.
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