A Eukaryotic Circuit for Secretion-coupled Cellular Autonomy

Abstract

SUMMARYCancers represent complex autonomous robust systems, displaying interconnectivity with feedback control. Autonomous growth is fueled by a cancer cell’s ability to ‘secrete-and-sense’ growth factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giabg and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimuli-proportionate secretion. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy.GRAPHIC ABSTRACTIn BriefThis work delivers an experimentally validated dynamical systems model of the cooperativity between two distinct classes of biological switches in eukaryotic cells and reveals the basis of secretion-coupled cellular autonomy in cancer.HIGHLIGHTSModeling and experimental approaches were used to dissect a coupled GTPase circuitCoupling enables closed loop feedback and mutual control of GTPasesCoupling generates dose response alignment behavior of sensing and secretion.Coupling is critical for multiscale feedback control to achieve secretion-coupled autonomy.