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 cell’s ability to ‘secrete-and-sense’: 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 Giαβγ 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. ![Figure][1] In Brief This 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 secrete-and-sense autonomy in cancer. HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest. * GIV : Gα-interacting Vesicle-associated protein GEM : guanine nucleotide exchange modulator DoRA : dose-response alignment Arf1 : ADP-ribosylation factor-1 EGF : Epidermal growth factor ER : endoplasmic reticulum ERGIC : ER-Golgi Intermediate Compartment CLC : closed loop control GGA : Golgi-localized, γ-ear-containing, Arf -binding protein [1]: pending:yes