Inhibition of kras-derived exosomes downregulates immunosuppressive BACH2/GATA-3 expression via RIP-3 dependent necroptosis and miR-146/miR-210 modulation - 08/01/20
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Graphical abstract |
Highlights |
• | Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice. |
• | Kras secreted exosomes can shift pyruvate/PKM2 dependent metabolism and thus maintain tumor cell metabolic chemoresistance. |
• | Inhibition of Kras exosomal mechanism triggers activation of the RIP1/RIP3 necrosome complex. |
• | Kras exosomal targeting prevents miR146a/miR-210-related immunosuppression and enhances T-cell Th1 immune response. |
• | Exosomal Kras inhibition downregulates BACH2/GATA3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism. |
Abstract |
Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.
Le texte complet de cet article est disponible en PDF.Abbreviations : SMARCE1, NCOR1, BACH2, GATA-3, PKM2, FOXP3, NSCLC, HIF-1A, RIP1, NF-κB, MLKL, TNF-a, ARID1A, HK-2
Keywords : Kras, Exosomes, BACH2, Necroptosis, miR-146/miR-210
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