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Stress-induced ADGRL4 orchestrates tumor dormancy and relapse via Gαs-YAP1 signaling and angiogenesis

ABSTRACT: 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 Gαs to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 forms a transcriptional complex with β-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE311934 | GEO | 2026/02/06

REPOSITORIES: GEO

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Stress-induced ADGRL4 orchestrates tumor dormancy and relapse via Gαs-YAP1 signaling and angiogenesis

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