A Eukaryotic Circuit for Secrete-and-Sense Autonomy

Cancers represent complex autonomous robust systems, displaying interconnectivity with feedback control. Autonomy is fueled by a cancer cell9s ability to 9secrete-and-sense9: 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 secrete-and-sense autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Gi; and their corresponding GAPs and GEFs are coupled by the scaffold protein GIV/Girdin, a bona fide metastasis-related protein across a variety of solid tumors. 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 survival that is self-sustained by autocrine secretion. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve autocrine autonomy.