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 mechanism 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 β4; and induction of integrin β4 endocytosis and degradation, we hypothesized ADAM9 induced cancer metastasis is through the regulation of hemidesmosome disassembly and integrin β4 turnover. Therefore, the purpose of this study is to characterize whether ADAM9 is a important but underappreciated regulator of hemidesmosome complex involved in cancer distant metastasis. There are three aims in this project. 1) To evaluate ADAM9 and ITGB4 interactions and their role in lamellipodia formation and integrin β4 relocation, 2) To analyze the role of ADAM9 in the regulation of integrin β4 internalization, endocytosis, degradation and/or recycling. 3) To characterize the ADAM9 domains that are crucial for integrin β4-dependent prostate cancer metastasis as potential therapeutic targets. 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.
|Effective start/end date||8/1/16 → 7/31/17|
- extracellular matrix
- tumor microenvironment
- cancer migration
- cancer metastasis
- cancer therapy
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