Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K

摘要

Author summary Complex diseases such as cancer often alter more than one facet of a cells function. In addition to breakdown in individual functions, cancer progression leads to unhealthy combinations of cellular behaviors. For example, cancer cells rely on non-physiological combinations of cell functions drawn from an arsenal that includes proliferation, resistance to apoptosis, migration, and blood vessel recruitment. These functions are all critical to health or development, often in a different tissue than that of the tumor. Building predictive models that reproduce this coordination of functions could greatly boost our ability to combat complex disease. Here, we develop a large network model of the processes that control a mammalian cells life and death. Our model reproduces a non-intuitive oscillation in a key cell division pathway (PI3K/AKT1), along with the cell-cycle altering effect of its oncogenic activation. To do this, we incorporate the role of Polo-like kinase 1 (mitotic driver, chemotherapy target) and model mitotic failure when Plk1 is blocked. Finally, we offer testable predictions on the unexplored drivers of PI3K oscillations, their timing with respect to division, and the mechanism by which hyperactive PI3K leads to genome-level defects. Thus, our work can aid development of powerful models that cover most processes that go awry when cells transition into malignancy.