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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA189764-02
Application #
8928485
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
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