Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy

William L. Harryman, Jaime M.C. Gard, Kelvin W. Pond, Skyler J. Simpson, Lucas H. Heppner, Daniel Hernandez-Cortes, Andrew S. Little, Jennifer M. Eschbacher, Anne E Cress

Research output: Contribution to journalArticle

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Abstract

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 (γH2AX, 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 α6 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 γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX 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 γH2AX response. β1 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.

Original languageEnglish (US)
Pages (from-to)919-927
Number of pages9
JournalNeoplasia (United States)
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2017

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Chordoma
Ionizing Radiation
Integrins
Phenotype
DNA Damage
Cell Adhesion
Laminin Receptors
Radiation Dosage
Neoplasms
Blocking Antibodies
Skull Base
Tumor Cell Line
Fluorescence Microscopy
Prostate
Cell Survival
Cell Cycle
Flow Cytometry
Radiation
Neoplasm Metastasis
Ligands

ASJC Scopus subject areas

  • Cancer Research

Cite this

Harryman, W. L., Gard, J. M. C., Pond, K. W., Simpson, S. J., Heppner, L. H., Hernandez-Cortes, D., ... Cress, A. E. (2017). Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy. Neoplasia (United States), 19(11), 919-927. https://doi.org/10.1016/j.neo.2017.08.005

Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy. / Harryman, William L.; Gard, Jaime M.C.; Pond, Kelvin W.; Simpson, Skyler J.; Heppner, Lucas H.; Hernandez-Cortes, Daniel; Little, Andrew S.; Eschbacher, Jennifer M.; Cress, Anne E.

In: Neoplasia (United States), Vol. 19, No. 11, 01.11.2017, p. 919-927.

Research output: Contribution to journalArticle

Harryman, WL, Gard, JMC, Pond, KW, Simpson, SJ, Heppner, LH, Hernandez-Cortes, D, Little, AS, Eschbacher, JM & Cress, AE 2017, 'Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy', Neoplasia (United States), vol. 19, no. 11, pp. 919-927. https://doi.org/10.1016/j.neo.2017.08.005
Harryman, William L. ; Gard, Jaime M.C. ; Pond, Kelvin W. ; Simpson, Skyler J. ; Heppner, Lucas H. ; Hernandez-Cortes, Daniel ; Little, Andrew S. ; Eschbacher, Jennifer M. ; Cress, Anne E. / Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy. In: Neoplasia (United States). 2017 ; Vol. 19, No. 11. pp. 919-927.
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abstract = "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 (γH2AX, 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 α6 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 γH2AX and pKAP1 expression in all cell lines. However, nearly 50{\%} of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15{\%} of U-CH1 clustered cells were γH2AX 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 γH2AX response. β1 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.",
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