Experimentally-driven mathematical model to understand the effects of matrix deprivation in breast cancer metastasis.

Normal epithelial cells receive proper signals for growth and survival from attachment to the underlying extracellular matrix (ECM). They perceive detachment from the ECM as a stress and die - a phenomenon termed as 'anoikis'. However, metastatic cancer cells acquire anoikis-resistance and circulate through the blood and lymphatics to seed metastasis. Under normal (adherent) growth conditions, the serine-threonine protein kinase Akt stimulates protein synthesis and cell growth, maintaining an anabolic state in the cancer cell. In contrast, previously we showed that the stress due to matrix deprivation is sensed by yet another serine-threonine kinase, AMP-activated protein kinase (AMPK), that inhibits anabolic pathways while promoting catabolic processes. We illustrated a switch from Akt/AMPK in adherent condition to AMPK/Akt in matrix-detached condition, with consequent metabolic switching from an anabolic to a catabolic state, which aids cancer cell stress-survival. In this study, we utilized these experimental data and developed a deterministic ordinary differential equation (ODE)-based mechanistic mathematical model to mimic attachment-detachment signaling network. To do so, we used the framework of insulin-glucagon signaling with consequent metabolic shifts to capture the pathophysiology of matrix-deprived state in breast cancer cells. Using the developed metastatic breast cancer signaling (MBCS) model, we identified perturbation of several signaling proteins such as IRS, PI3K, PKC, GLUT1, IP3, DAG, PKA, cAMP, and PDE3 upon matrix deprivation. Further, in silico molecular perturbations revealed that several feedback/crosstalks like DAG to PKC, PKC to IRS, S6K1 to IRS, cAMP to PKA, and AMPK to Akt are essential for the metabolic switching in matrix-deprived cancer cells. AMPK knockdown simulations identified a crucial role for AMPK in maintaining these adaptive changes. Thus, this mathematical framework provides insights on attachment-detachment signaling with metabolic adaptations that promote cancer metastasis.