Analyses the Role of ADAM9-Hemidesmosome Components Interaction in Malignant Cancer Metastasis and Future Therapeutic Strategy

Metastasis is major caused of fatality during malignant cancer progression. Understanding the principle mechanisms of cancer metastasis is important for developing strategies to prevent lethal phenotypic cancer progression and associated complications. Migration and invasion are decisive steps in initiating cancer metastasis. These involved the releasing of migrating cancer cells from primary loci with the lost of normal epithelium characteristics, including degrading proteins involved in the formation of tight junction, desmosome and hemidesmosome complexes that holds cells together and maintain cell polarity. In addition, lost of hemidesmosome has been showed to correlate with skin blistering diseases, Bullous Pemphigoid, in which epithelium released from basement membrane. Evidences indicated ADAM9 could enhance the disease by cleavage of BP180 on cell surface. Recently, several members of the ADAM (A Disintegrin And Metalloprotease) proteins have been implicated in human tumorigenesis. A series of studies done by our group revealed a vital role of ADAM9 in malignant cancer progression, including cancer metastasis and therapeutic-resistance of prostate cancer cells. Furthermore, we have showed ADAM9 as important biomarker for early diagnosis of lethal recurrence after androgen ablation therapy. Although clinical observations support the oncogenic function of ADAM9 in cancer progression, to date, the precise mechanisms by which ADAM9 facilitates cancer metastasis is not fully understood. Structurally, ADAM has been implicated as a potential integrin ligand through its disintegrin domain, suggesting a regulatory role of ADAM9 in integrin-dependent cell migration. In the light of our preliminary results: ablation of ADAM9 expression decreased invasiveness of prostate cancer cells; ADAM9 physically interacted with hemidesmosome components, plectin, BP180 and integrin α6β4; and induction of integrin β4 endocytosis and degradation, we hypothesized ADAM9 supporting cancer metastasis by modulating hemidesmosome components mediated anchorage of cancer cells during initiating of cell migration. Therefore, the purpose of this study is to characterize whether ADAM9 is a potential but unexplored component of hemidesmosome complex involved in cancer distant metastasis. There are three aims in this project. 1) To evaluate hemidesmosome components and ADAM9 interaction in the regulation of actin polymerization and invasion of cancer cells. 2) To analyze the role of ADAM9 in the regulation of hemidesmosomal internalization, degradation and/or recycling. 3) To analyze the potential therapeutic strategy by blocking the ADAM9 tropism dependent hemidesmosome or integrin interaction during cancer metastasis. The novelty of this project is the analyses of interplay between ADAM9 and hemidesmosome components in controlling cancer cell invasion, migration and distant metastasis, as well as therapeutic evaluation. The success of this proposal will help us better understand mechanisms of cell-extracellular matrix interactions in regulating cancer cell metastasis, especially the degradation of integrins of epithelium. These studies will provide the basis for design of ADAM9/hemidesmosome-based targeted therapy to combat the lethal phenotype of cancer metastasis.