Does frequency-dependent cell proliferation exhibit a Fano-type resonance?

We examined PC12 cell proliferation in environments with temporally varying epidermal growth factor concentrations by means of a microfluidic system. Our measurements revealed frequency-dependent cell behaviour over an observation period of three days. The cell population either increased, decreased or remained constant depending on the frequency of epidermal growth factor applied. A plot of the apparent proliferation rate as a function of growth-factor frequency was mathematically described by the Fano line-shape formula. In the context of linear response theory, these results imply that the PC12 cells compute zero, first and second-order time derivatives of the ligand concentration and utilise this information to decide to proliferate or die. We discuss a physical model based on periodic forcing of coupled oscillators that accounts for these observations. Our results and analysis suggest the possibility to influence cell fate by controlling the dynamics of the extracellular environment.