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Unique structural configuration of EV-DNA primes Kupffer cell-mediated anti-tumor immunity to prevent metastatic progression

ABSTRACT: Extracellular vesicles (EVs) transport biomolecules that mediate intercellular communication. We previously showed that EVs contain DNA (EV-DNA) representing the entire genome. However, the mechanism of EV-DNA packaging and its role in cancer remains elusive. Here, we demonstrate that the majority of DNA is localized on the vesicle surface and associated with uniquely modified and cleaved histones. We conducted a genome-wide CRISPR knockout screen, which revealed that immune developmental pathways and genes, including APAF1 and NCF1, regulated EV-DNA packaging. We further demonstrated in colorectal cancer models that uptake of EVs and EV-DNA by Kupffer cells (KC) activated DNA damage responses. This activation re-wired KC cytokine production and generated tertiary lymphoid structures in pre-metastatic livers, thereby suppressing metastasis. Conversely, loss of APAF1 decreased EV-DNA packaging and promoted liver metastasis. Quantifying EV-DNA in colorectal cancer biopsies revealed that EV-DNA could possibly serve as a predictive biomarker for metastatic risk.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD056104 | Pride | 2024-09-23

REPOSITORIES: Pride

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	20200717_Simone_Jake_HCT116_Exosome_rep-1.raw	Raw
	20200717_Simone_Jake_HCT116_Exosome_rep-2.raw	Raw
	20200717_Simone_Jake_HCT116_Exosome_rep-3.raw	Raw
	20200717_Simone_Jake_HCT116_Histone_rep-1.raw	Raw
	20200717_Simone_Jake_HCT116_Histone_rep-2.raw	Raw

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