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Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression

Bingjie Guan, Youdong Liu, Bowen Xie, Senlin Zhao, Abudushalamu Yalikun, Weiwei Chen, Menghua Zhou, Qi Gu and Dongwang Yan (yandw70@163.com)
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Bingjie Guan: Shanghai Jiao Tong University School of Medicine
Youdong Liu: Shanghai Jiao Tong University School of Medicine
Bowen Xie: Shanghai Jiao Tong University School of Medicine
Senlin Zhao: Fudan University Shanghai Cancer Center
Abudushalamu Yalikun: Shanghai Jiao Tong University School of Medicine
Weiwei Chen: Shanghai Jiao Tong University School of Medicine
Menghua Zhou: Shanghai Jiao Tong University School of Medicine
Qi Gu: Shanghai Jiao Tong University School of Medicine
Dongwang Yan: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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 TGFβ1 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 TGFβ1 expression and promoting tumor progression via the TGFβ/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.

Date: 2024
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DOI: 10.1038/s41467-024-48100-y

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