Deciphering the physical properties of cell fate decision making in mTOR signaling

The mammalian target of rapamycin (mTOR) signaling pathway, a crucial nutrient sensor in cells, plays pivotal roles in maintaining metabolic homeostasis, cancer development, and aging-related physiological and pathological processes. Despite its significance, the regulatory mechanisms of mTOR signaling, particularly its physical properties, remain poorly understood. Here, we constructed an insulin-induced mTOR signaling model and identified time- and dose-dependent biphasic behaviors. Our findings demonstrate that the indirect negative feedback of mTORC1 on mTORC2 is central to generating these behaviors. By integrating concepts from potential landscape theory, entropy production, and dominant kinetic paths, we quantified the transitions between various cellular states-normal, tumor, prosurvival, and aging-from a physical properties perspective. Potential landscape and entropy analyses suggest that the levels of mTORC1 and mTORC2 regulate cellular fate transitions between multiple attractors, including normal, tumor, prosurvival, and aging. Dominant kinetic path analysis further revealed that the transition from normal state to tumor state requires crossing the aging state barrier, which inhibits tumor formation. The optimal transition paths between different states are irreversible. Despite the minimal action along these paths, the system still drives the transition paths to bypass the saddle points between the lowest states. This phenomenon arises from the driving forces in nonequilibrium systems, which depend not only on gradient forces within potential wells but also on curl forces. Our study provides new insights into the nonequilibrium dynamics of mTOR signaling in cell fate decisions. It enhances our understanding of tumorigenesis and aging from a physical perspective, offers guidance for targeted and personalized treatments, and suggests potential clues to uncover the physiological and pathological significance of mTOR signaling.