Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGF beta 1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGF beta 1 expression and promoting tumor progression via the TGF beta/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC. The interaction between colon cancer cells and colonic epithelial cells (CECs) is critical yet not well-known. Here, the authors show that tumor extracellular vesicles mediate mitochondrial DNA transfer to CECs, initiating mitochondrial activation and RelA-induced TGF beta 1 expression, leading to tumor progression.
[1]Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China.
[2]Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, Shanghai, Peoples R China.
[3]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.
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