Title | Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Wortzel I, Seo Y, Akano I, Shaashua L, Tobias GCardial, Hebert J, Kim K-A, Kim DA, Dror S, Liu Y, Azrak GCampbell, Cioffi M, Johnson KEnnu, Hennika T, Twerski MZisha, Kushner A, Math R, Han YDae, Han DHoon, Jung M, Park J, Paik S, Shin J-S, Lee MGoo, Russo MVincenzo, Zakheim D, Barnes J, Mehta S, Manova K, Schwartz RE, Thakur BKumar, Boudreau N, Matei I, Zhang H, Sidoli S, Bromberg J, David Y, Kim HSang, Lyden D |
Journal | Nat Cancer |
Date Published | 2024 Dec 03 |
ISSN | 2662-1347 |
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 genomic EV-DNA packaging and its role in cancer remain elusive. We now demonstrate that EV-DNA is predominantly localized on the vesicle surface and associated with uniquely modified and cleaved histones. Moreover, a genome-wide clustered regularly interspaced short palindromic repeats knockout screen revealed that immune developmental pathways and genes, including apoptotic peptidase activating factor 1 (APAF1) and neutrophil cytosolic factor 1 (NCF1), regulate EV-DNA packaging. Furthermore, in colorectal cancer models, uptake of EV-DNA by pre-metastatic liver Kupffer cells (KCs) activated DNA damage responses. This activation rewired KC cytokine production and promoted the formation of tertiary lymphoid structures, thereby suppressing liver metastasis. Conversely, loss of APAF1 decreased EV-DNA packaging and promoted liver metastasis. Importantly, colorectal cancer biopsy EV-DNA secretion could serve as a predictive biomarker for postoperative metastasis. Taken together, our findings indicate that uniquely chromatinized EV-DNA induces antitumor immunity. |
DOI | 10.1038/s43018-024-00862-6 |
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Alternate Journal | Nat Cancer |
PubMed ID | 39627554 |
PubMed Central ID | 6652179 |
Grant List | CA224175 (D.L.), CA210240 (D.L.), CA232093 (D.L.), CA207983 (D.L.), CA169538 (D.L.) and CA218513 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / 23-0105 / AICR_ / Worldwide Cancer Research / United Kingdom HI19C1330 / / Korea Health Industry Development Institute (KHIDI) / CA218513 / / Center for Strategic Scientific Initiatives, National Cancer Institute (NCI Center for Strategic Scientific Initiatives) / P30 CA008748 / CA / NCI NIH HHS / United States P50 CA192937 / CA / NCI NIH HHS / United States R35 GM138386 / GM / NIGMS NIH HHS / United States 20012443 / / Ministry of Trade, Industry and Energy (Ministry of Trade, Industry and Energy, Korea) / |