Growth factor receptor and β1 integrin signaling differentially regulate basal clonogenicity and radiation survival of fibroblasts via a modulation of cell cycling

Cell adhesion to extracellular matrix proteins mediates resistance to radio- and chemotherapy by activating integrin signal-
ing. In addition, mutual and cooperative interactions between integrin and growth factor receptor signaling contribute to
the cellular radiation response. Here, we investigate to which extend the crosstalk between β1 integrins and growth factor
receptor signaling determines the cellular radiation response of fibroblasts by assessing clonogenic survival and cell cycling.
By utilizing growth factor signaling competent and either β1 integrin wildtype GD25β1A fibroblasts or β1 integrin mutant,
signaling incompetent GD25β1B fibroblasts, we show basal clonogenic survival to depend on growth factor receptor but not
integrin signaling. Our data further suggest the cooperation between β1 integrins and growth factor receptors to be critical
for enhancing the radiation-induced G2/M cell cycle block leading to improved clonogenic radiation survival. By pharmaco-
logical inhibition of EGFR and PI3K, we additionally show that the essential contribution of EGFR signaling to radiogenic
G2/M cell cycle arrest depends on the co-activation of the β1 integrin signaling axis, but occurs independent of PI3K. Taken
together, elucidation of the signaling circuitry underlying the EGFR/β1 integrin crosstalk may support the development of
advanced molecular targeted therapies for radiation oncology.