Unfolded protein response kinase PERK supports survival and metastasis of circulating tumor cell clusters via SAM synthesis and H3K4me3‐dependent PDGFB signaling

Abstract Background Metastasis is the leading cause of cancer‐related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream. Methods CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient‐derived xenograft (PDX), cell line‐derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA‐sequencing (RNA‐seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA‐seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient‐derived CTCs and the PDX model. Results CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R‐like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S‐adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet‐derived growth factor B ( PDGFB ) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathway via platelet‐derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters. Conclusions Our findings revealed a PERK/MAT2A/PDGFB axis that confers adaptive survival capabilities to CTC clusters in the bloodstream. Targeting this survival signaling pathway represents a promising therapeutic strategy for metastatic cancer.