Biochimica et biophysica acta. Molecular basis of disease · 2026
CD36 regulates metabolic reprogramming and early cluster formation of suspension cancer cells during metastatic progression.
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Kwon Doru, Park Hyun Woo, Choi Junjeong
Аннотация
INTRODUCTION: Circulating tumor cell (CTC) clusters are potent mediators of metastasis, exhibiting dramatically enhanced survival and colonization potential compared to single CTCs. However, the molecular and metabolic programs that initiate cluster formation remain poorly defined. CD36 is known to be critical for metastasis and metabolism. However, its regulatory role during the Adherent-to-Suspension Transition (AST) and subsequent CTC clustering remains unclear. This study aimed to elucidate how CD36 orchestrates early clustering of AST-derived cancer cells and to explore its potential as a stage-specific therapeutic vulnerability.
METHODS: We utilized an in vitro AST-Cluster Transition Model with cancer cells, monitored by live-cell imaging. The impact of CD36, glycolysis, and ROS inhibition on cluster dynamics and viability was assessed. Efficacy was confirmed in vivo using a cluster-driven metastasis mouse model and patient data (CTC transcriptomes, METABRIC cohort) were analyzed for metabolic and prognostic relevance.
RESULTS: We found biphasic CD36 expression (upregulated in AST cells, decreased upon clustering) concurrent with a metabolic shift from OXPHOS to glycolysis under hypoxia. This metabolic reprogramming was sustained by the AKT, AMPK, and HIF1α axes. CD36 inhibition impaired early cluster formation, which was accompanied by decreased expression of junctional proteins, and was sufficient to reduce cluster-driven lung metastases in vivo. Patient data linked similar metabolic remodeling signatures, and high expression of CD36 and JUP was associated with poorer early survival.
CONCLUSIONS: This study identifies CD36 as a dynamic regulator linking AST to clustering and metabolic adaptation. CD36 blockade effectively suppresses cluster-driven colonization, revealing CD36 as a tractable, stage-specific therapeutic target to intercept metastatic dissemination at its earliest, most vulnerable stage.
METHODS: We utilized an in vitro AST-Cluster Transition Model with cancer cells, monitored by live-cell imaging. The impact of CD36, glycolysis, and ROS inhibition on cluster dynamics and viability was assessed. Efficacy was confirmed in vivo using a cluster-driven metastasis mouse model and patient data (CTC transcriptomes, METABRIC cohort) were analyzed for metabolic and prognostic relevance.
RESULTS: We found biphasic CD36 expression (upregulated in AST cells, decreased upon clustering) concurrent with a metabolic shift from OXPHOS to glycolysis under hypoxia. This metabolic reprogramming was sustained by the AKT, AMPK, and HIF1α axes. CD36 inhibition impaired early cluster formation, which was accompanied by decreased expression of junctional proteins, and was sufficient to reduce cluster-driven lung metastases in vivo. Patient data linked similar metabolic remodeling signatures, and high expression of CD36 and JUP was associated with poorer early survival.
CONCLUSIONS: This study identifies CD36 as a dynamic regulator linking AST to clustering and metabolic adaptation. CD36 blockade effectively suppresses cluster-driven colonization, revealing CD36 as a tractable, stage-specific therapeutic target to intercept metastatic dissemination at its earliest, most vulnerable stage.