Balance between autophagy and apoptosis determines anoikis resistance: a mathematical model on cell fate

Abstract

Although several cancer cells are shed into circulation, most die due to stress, including loss of matrix attachment which triggers anoikis. A subset, however, acquires anoikis resistance, and survives to seed metastasis. How matrix-deprived cancer cells balance autophagy and apoptosis to decide cell fate remains unclear. Here, we formulated a deterministic ordinary differential equation (ODE)-based model of Akt-AMPK-ERK signal interaction to study this balance. Simulations revealed that high AMPK activity, with heterogenous ERK and low pAkt levels promote survival, whereas high pAkt shifts towards apoptosis. Molecular perturbation analyses revealed a signaling hierarchy in which Akt dominates over AMPK which further dominates over ERK. This model further predicts that the extent of autophagy determines apoptotic outcomes with high autophagy favoring survival of matrix-detached MDA-MB-231 cells. Together, our study provides a mathematical framework linking signaling dynamics to cell-fate decisions governing anoikis resistance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/658583v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@d40fdorg.highwire.dtl.DTLVardef@25a839org.highwire.dtl.DTLVardef@475401org.highwire.dtl.DTLVardef@dc4e6b_HPS_FORMAT_FIGEXP M_FIG C_FIG