Construction of a Waddington-like landscape model that can guide clinical exploration of p53-dynamics-activating parameters in the face of divergent p53 dynamics

Abstract

The primary strategy of radiotherapies is to manipulate cell fate decision, a process mainly regulated by a spectrum of p53 dynamics. Based on their biological relevance, we analytically categorize the range of p53 levels into seven distinct level-forms, leading to the identification of eleven non-chaotic phenomena of p53 level-form dynamics. The superimposing of cell fate attractors on the co-dimension two bifurcation diagram of eleven p53 level-form dynamics, under quasi-steady state assumption, provides a mechanistic tool that can be posted as a Waddington-like landscape model for cell fate regulation by p53 dynamics. In the proposed model, the (location of) cell is represented as a control point in the bifurcation diagram representing a flattened landscape composed of 11 distinct behavioral regions, and the effort that moves the cell on the landscape is exerted by accumulating death factors upon DNA damage. Further analysis reveals that intrinsically-resistant cancer attractors inevitably exist on the landscape, and cells might have evolved to use a safe operational area whose cusp bifurcation shape is contributing to robustness via hysteresis. We further reveal specific mechanisms through which tumors acquire resistance under therapy. The proposed landscape model can be put to productive use via a reverse control methodology. The reconstruction of cancer-specific landscape can inform the design of personalized p53-dynamics-based drug combination strategies suffering from the combinatorial explosion of target parameters and the divergent p53 dynamics. We conclude that the reverse control of the proposed landscape model has the potential to bridge the gap between theoretical and clinical studies of p53 dynamics for p53-dynamics-based cancer therapies.