Modeling G1 phase of mammalian cell cycle: cell fate determination and cancer onset

Upon their exit from mitosis, mammalian cells enter a G1 phase during which they acutely sense all sorts of environmental stimuli. On the basis of these signals, they decide whether to undergo division, quiescence, differentiation, senescence or apoptosis. Failures in this process may lead to cancer. In this study, I questioned whether, despite the complexity of the G1 regulatory network, simple organizing principles might be identified that could explain how specific input signals are converted into appropriate cell fates. For this purpose, a mathematical model of the G1 regulatory network has been formulated using a simplified description of activities linked to signal transduction, cell growth, cell division and cell death. Bifurcation analysis of the model revealed the existence of multistability between several attractor states corresponding to G0 -arrest, G1 -arrest, S-phase entry and apoptosis cell fates.
Finally, I will discuss the result of this modeling study from different perspectives: (i) from a modeler's perspective, how to design a model that captures the qualitative behavior of a biological process or system; (ii) from an engineer's perspective, how feedback and feedforward loops are combined within a regulatory network to drive the signal-dependent switch between distinct cellular processes; (iii) from a biologist's perspective, how the control of cell fate determination have evolved in multicellular organisms and how it could fail thereby enabling the emergence of cancers.