Stress-Induced ADGRL4 Orchestrates Tumor Progression and Metastasis by Inhibiting YAP1 Signaling and Activating Angiogenesis

G protein-coupled receptors (GPCR) are cell surface signal transducers that regulate diverse physiologic and pathologic processes. In this study, we identified the adhesion GPCR family member ADGRL4 as a key orchestrator of tumor adaptation to stress. Cellular stress induced ADGRL4 expression via the canonical JNK-ATF2/c-Jun pathway. Elevated ADGRL4 limited tumor expansion and enforced a tumor-suppressive state, whereas its loss accelerated tumor growth and metastasis. Mechanistically, stress-induced shedding of the N-terminal fragment activated the C-terminal fragment of ADGRL4, which coupled with Gαs to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 formed a transcriptional complex with β-catenin, reprogramming extracellular matrix signaling to bypass tumor suppression and drive growth. Notably, while restraining tumor growth by compromising proliferative activity, stress-induced ADGRL4 simultaneously diminished chemosensitivity and promoted angiogenesis, thereby heightening relapse risk. Thus, ADGRL4 emerges as a stress sensor that integrates YAP1 signaling with tumor angiogenesis to govern the balance between tumor-suppressing and tumor-promoting states, providing mechanistic insight into therapy-induced tumor progression. SIGNIFICANCE: Cellular survival stress induces expression of ADGRL4 that signals intracellularly to suppress YAP1/β-catenin-driven protumorigenic activities and acts extracellularly to promote angiogenesis, thereby exerting dual tumor-suppressive and relapse-promoting effects.