Abstract B65: Proteolytic shedding of the cell adhesion molecule ALCAM generates a spatial and context-dependent heterogeneity important for metastasis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-01, Vol.75 (1_Supplement), p.B65-B65
• Main Authors: Hansen, Amanda G., Hebron, Katie, Palmer, Trenis D., Arnold, Shanna, Zijlstra, Andries
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.CHTME14-B65

Heterogeneity in the tumor microenvironment is dictated in part by context-dependent changes in cell-cell interactions. Subpopulations of tumor cells can responding to local micro-environmental changes in a manner that distinguishes them biochemically as well as behaviorally from the rest of the tumor. We identified such a phenomenon in the proteolytic shedding of the cell adhesion molecule ALCAM (Activated Leukocyte Cell Adhesion Molecule). ALCAM controls cell adhesion in a variety of cell types including T-cells, epithelial cells, neurons and endothelial cell. Although ALCAM mRNA is detected in all epithelial tissues and the tumors they give rise to, the detection of cell-surface ALCAM is highly variable, being strong in some regions of the tumor while completely absent in adjacent tumor cells. Through molecular analysis of cell-surface ALCAM we determined that this adhesion molecule is shed from the surface by ADAM17 in response to cytokines from the local milieu. Although ALCAM shedding is common in cancer, the loss of ALCAM greatly diminishes metastasis, thereby suggesting that ALCAM remains necessary for tumor progression. Indeed, ALCAM shedding supports a dynamic regulation of cell adhesion which, in turn, supports tumor cell dissemination. Considering that the proteolytic processing of ALCAM is functionally important in tumor progression, the detection of ALCAM shedding should be a molecular indicator of disease progression. Indeed, through analysis of retrospective patient cohorts, we demonstrated ALCAM shedding to be a prognostic indicator of disease progression in cancers of the colon, kidney and bladder. Our observations demonstrate that spatial and context-dependent heterogeneity can be accomplished through post-translational proteolysis of cell adhesion molecules. This process enables tumor cells to respond dynamically to the local milieu and disseminate to a more hospitable environment. Identifying this proteolysis in cancer patients through the detection of ALCAM shedding can predict metastatic progression and long-term patient outcome. Citation Format: Amanda G. Hansen, Katie Hebron, Trenis D. Palmer, Shanna Arnold, Andries Zijlstra. Proteolytic shedding of the cell adhesion molecule ALCAM generates a spatial and context-dependent heterogeneity important for metastasis.. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Canc