Cell clusters are programmed towards a reductive metabolic 1 state by adherence junctions

Solitary cells form stable clusters via cell-cell adhesion using adherens junctions. The role of these junctions in early cell-state changes as cells form clusters is unclear. Here, we uncover that the formation of cadherin junctions as cells cluster drives a ubiquitous metabolic reprogramming. This reprogramming enhances the pentose phosphate pathway (PPP) and NADPH production to augment a reductive state. Consequently, cell clusters stabilized by cadherin junctions have reduced intracellular reactive oxygen species (ROS), are resistant to exogenous ROS-inducing agents, and have reduced apoptotic markers. Mechanistically, this metabolic reprogramming is driven by the cadherin-dependent activation of NRF2. Blocking the cadherin junction-dependent metabolic program reverses clustered cells to resemble the solitary cell state, increasing cell death and enhancing sensitivity to exogenous ROS. These insights suggest a biochemical basis for adherens junctions mediating a reductive metabolic program as solitary cells form clusters, with implications for understanding multicellular organization and collective cell behavior.