%0 Journal Article
%T Targeting the Cohesive Cluster Phenotype in Chordoma via ¦Â1 Integrin Increases Ionizing Radiation Efficacy
%A Andrew S. Little
%A Anne E. Cress
%A Daniel Hernandez-Cortes
%A Jaime M.C. Gard
%A Jennifer M. Eschbacher
%A Kelvin W. Pond
%A Lucas H. Heppner
%A Skyler J. Simpson
%A William L. Harryman
%J Archive of "Neoplasia (New York, N.Y.)".
%D 2017
%R 10.1016/j.neo.2017.08.005
%X Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (¦ÃH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an ¦Á6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in ¦ÃH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by ¦ÃH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were ¦ÃH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved ¦ÃH2AX response. ¦Â1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614733/