Long-Term Goals: This proposal investigates mechanisms of tumor cell migration controlled by the cell surface adhesion molecule ALCAM (Activated Leukocyte Cell Adhesion Molecule). We found that ALCAM is required for metastasis of prostate cancer (PCa) to the bone and that increased proteolysis of its ectodomain corresponds to poor outcome for cancer patients. Our objective is to determine how the proteolysis of ALCAM contributes to PCa progression. The long-term goal is to use the molecular understanding of this process to improve the detection of disease progression and to identify suitable targets for therapeutic intervention.
Specific Aims : ALCAM is cleaved by both ADAM17 and ?-secretase, creating extracellular and intracellular fragments with potential biological activity relevant to tumor progression. The function of these fragments has yet to be explored.
The aims of this proposal include: 1. Determining the functional contribution of ALCAM proteolysis to PCa progression 2. Identifying gene expression changes associated with ALCAM proteolysis. Impact: Despite significant advances in the screening and treatment of PCa, the disease continues to be the second highest cause of cancer-related death in men. Better mechanistic understanding of tumor cell dissemination will improve detection of patients with molecularly advanced disease and identify new therapeutic targets that may be suitable for patients with metastatic disease. Research Training Program: The proposal outlines the training, collaborations, and resources that will help Kate reach her research goals and prepare her for a career as an independent scientist. Kate is receiving her didactic training in the department of Cancer Biology at Vanderbilt University (VU) through courses, seminars, and retreats. Her technical training will take place in the laboratories of Andries Zijlstra, Ph.D. and Simon Hayward, Ph.D. with aid from collaborating laboratories, giving her access to experts in models of PCa, bone biology and genomics. Clinical collaborators will direct clinic experience and training in PCa histopathology.VU cores offer access to state-of-the-art resources including animal imaging and next generation sequencing. Methods for Achieving Stated Goals: The contribution of ALCAM to PCa progression will be dissected using six structural variants of ALCAM. Tumor cells expressing these variants of ALCAM will be analyzed using in vitro and in vivo models of migration, invasion, metastasis, and survival. The clinical relevance of ALCAM proteolysis will be determined by analyzing previously collected tissue and fluid samples from PCa patients. Additionally, gene expression changes in response to ALCAM proteolysis will be analyzed by performing RNAseq on tumor cells expressing the ALCAM structural variants. ALCAM-mediated gene expression changes will be evaluated for correlation to outcome and identification of novel PCa therapeutic targets. Execution of the research proposal will provide Kate with the knowledge, clinical perspective and technical, communication, and critical thinking skills needed to be an excellent scientist and a leader in the field of cancer research.
The metastasis of cancer from the site of origin to distant vital organs is largely dependent on the motility of tumor cells. Therefore, molecular mechanisms of migration can both be an indicator of disease progression and a target for therapy. We propose that understanding the mechanism by which the cell adhesion molecule, ALCAM, contributes to prostate tumor dissemination will improve both detection and treatment of prostate cancer.
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