Abstract 54: Tumor dormancy in breast cancer cells: Identification of junctional adhesion molecule-A as a novel regulator
Authors: Sri HariKrishna Vellanki, Rodrigo G. Cruz, Katherine M. Sheehan, Elaine W. Kay, Ann M. Hopkins
Journal: Cancer Research (2018)

Abstract In tumor dormancy, a sub-population of tumor cells becomes quiescent but can re-enter the cell cycle upon certain environmental cues. The re-awakening of dormant populations has been associated with tumor cell proliferation and poor patient outcomes. Tumor dormancy can be modelled in vitro by exposing cancer cells on fibronectin-coated plates to bFGF-2, a mammary differentiation factor abundant in the bone marrow stroma, which causes partial re-differentiation, cell spreading and re-expression of integrin-α5β1. We have uncovered a novel potential role for the adhesion protein Junctional Adhesion Molecule-A (JAM-A) in tumor dormancy. JAM-A overexpression has previously been linked to increased risk of metastasis in breast cancer patients, and its expression regulates the angiogenic functions of bFGF-2. Furthermore, since loss of JAM-A downregulates the α5β1 downstream effector FAK, we hypothesized that JAM-A is required for maintenance of tumor dormancy. To investigate this, JAM-A was transiently silenced in MCF-7 breast cancer cells grown on fibronectin-coated plates and exposed to FGF-2. JAM-silenced cells exhibited expressional downregulations in integrin-α5β1 and FAK proteins, and failed to exhibit the cortical actin redistribution and morphological spreading which characterize dormant cells. in parallel, pharmacologically-induced loss of JAM-A (using an anti-tumor antibiotic) prevented tumor dormancy and was cytotoxic to dormant cells. We next investigated a potential relationship between JAM-A expression and pro-inflammatory cytokines linked with the re-awakening of dormant cells in post-menopausal women. Exposure of MCF-7 cells to IL-1β, TNF-α, IL-6 and IL-8 increased the protein expression of matrix metalloproteinase ADAM17, which in turn caused JAM-A cleavage and loss from the cell membrane. Analysis of bone metastasis sections from post-menopausal breast cancer patients revealed significant heterogeneity in JAM-A expression, with some regions strongly positive for JAM-A while other regions were negative. Nonetheless, 20/24 metastatic sections expressed either moderate or high JAM-A levels, suggesting that even if cells transiently lose JAM-A to reawaken from tumor dormancy, they may later acquire high JAM-A expression during disease progression. The fact that JAM-high dormant cells had high Aldefluor activity, a feature of stemness, might also support an important role for JAM-A in tumor evolution or progression. To conclude, our data support a model whereby JAM-A is important for the maintenance of dormancy in breast cancer cells in a simulated bone marrow microenvironment, and represents a novel therapeutic target worthy of investigation in breast cancer. This work was financially supported by Science Foundation Ireland (grant 13/IA/1994 to AMH). Citation Format: Sri HariKrishna Vellanki, Rodrigo G. Cruz, Katherine M. Sheehan, Elaine W. Kay, Ann M. Hopkins. Tumor dormancy in breast cancer cells: Identification of junctional adhesion molecule-A as a novel regulator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 54.