Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFß1-mediated tumor progression.
Nat Commun
; 15(1): 3653, 2024 Apr 30.
Article
em En
| MEDLINE
| ID: mdl-38688896
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 TGFß1 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 TGFß1 expression and promoting tumor progression via the TGFß/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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
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Espécies Reativas de Oxigênio
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Neoplasias do Colo
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Progressão da Doença
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Células Epiteliais
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Fator de Crescimento Transformador beta1
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Genoma Mitocondrial
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Vesículas Extracelulares
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article