Stress-induced ADGRL4 orchestrates tumor dormancy and relapse via Gas-YAP1 signaling and angiogenesis
Adhesion G protein-coupled receptors (aGPCRs), the second-largest GPCR family, remain poorly understood due to their structural complexity. Here, we identify the member ADGRL4 as a key orchestrator of tumor adaptation to stress. Cellular stress induces ADGRL4 expression via the canonical JNK-ATF2/c-Jun pathway. Elevated ADGRL4 suppresses tumor expansion and enforces a dormancy-like state, whereas its loss accelerates tumor growth and metastasis. Mechanistically, stress-induced shedding of the N-terminal fragment (NTF) activates the C-terminal fragment (CTF) of ADGRL4, which couples with Gas to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 forms a transcriptional complex with ß-catenin, reprograming the extracellular matrix (ECM) signaling to bypass tumor dormancy and drive tumor expansion. Notably, stress-induced ADGRL4 exerts dual effects: while restraining tumor growth through dormancy enforcement, it simultaneously diminishes chemosensitivity and promotes angiogenesis, thereby heightening relapse risk. Thus, ADGRL4 emerges as a stress sensor that integrates YAP1 signaling with tumor angiogenesis to govern the balance between dormancy and relapse, providing mechanistic insight into therapy-induced tumor progression. Overall design: RNA-seq profiling of control B16 (Con) cells and knockdown derivatives (KD1 and KD2) was conducted using three biological replicates per group.