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@ARTICLE{Cheytan:299575,
      author       = {T. Cheytan$^*$ and M. Schneider$^*$ and R. Würth$^*$ and
                      P. Schwerd-Kleine$^*$ and E. Gutjahr$^*$ and V. Thewes$^*$
                      and L. L. Michel and R. Weber$^*$ and T. Vorberg$^*$ and S.
                      Lohr$^*$ and K. Nitschke and M. Neßling$^*$ and P.
                      Lichter$^*$ and A. Schneeweiss and K. Richter$^*$ and D.
                      Helm$^*$ and M. Sprick$^*$ and A. Trumpp$^*$},
      title        = {{S}mall extracellular vesicles and particles (s{EVP}s)
                      derived from tumor-free pre-metastatic organs promote breast
                      cancer metastasis and support organotropism.},
      journal      = {Molecular cancer},
      volume       = {24},
      number       = {1},
      issn         = {1476-4598},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-00516},
      pages        = {72},
      year         = {2025},
      note         = {DKFZ-ZMBH Alliance / #EA:A010#LA:A010#},
      abstract     = {Metastatic breast cancer remains largely incurable, partly
                      due to our incomplete understanding of its intricate
                      underlying mechanisms. Notably, intercellular communication
                      mediated by small extracellular vesicles and particles
                      (sEVPs) has emerged as a key feature of metastasis. While
                      tumor-derived sEVPs have been extensively studied and are
                      known to be pro-metastatic, the role of sEVPs from
                      metastasis-prone normal tissue sites remains primarily
                      undefined. Here, we characterized and studied the function
                      of sEVPs secreted from tumor-free pre-metastatic organs
                      (TuFMO-sEVPs) such as the brain and lungs in both
                      immunocompetent and patient-derived xenograft models.
                      TuFMO-sEVPs from the brain of mammary tumor-bearing mice
                      were found to have a distinct protein content as compared to
                      brain-sEVPs from tumor-free mice, suggesting that the
                      primary tumor can systemically influence the cargo of
                      TuFMO-sEVPs. Importantly, mice orthotopically injected with
                      breast cancer cells which had been educated with either
                      brain or lung TuFMO-sEVPs prior to transplantation showed
                      significantly increased metastasis to the respective organ.
                      We further demonstrated that TuFMO-sEVPs induced the
                      expression of the enzyme dihydrofolate reductase (DHFR) upon
                      uptake by breast cancer cells, leading to their enhanced
                      metastatic capacity. Organ-specific signatures generated
                      from TuFMO-sEVP educated tumor cells were found to be
                      increased in metastatic samples from breast cancer patients
                      as compared to the primary tumor or normal tissue samples
                      and these signatures also significantly correlated with
                      poorer patient outcome. Collectively, our data reveals a
                      novel facet of the metastatic cascade, implicating a role
                      for TuFMO-sEVPs in directing metastasis and providing a
                      potential therapeutic strategy for targeting this process.},
      subtyp        = {Letter},
      keywords     = {Animals / Humans / Female / Mice / Extracellular Vesicles:
                      metabolism / Breast Neoplasms: pathology / Breast Neoplasms:
                      metabolism / Cell Line, Tumor / Neoplasm Metastasis / Lung
                      Neoplasms: metabolism / Lung Neoplasms: pathology / Lung
                      Neoplasms: secondary / Xenograft Model Antitumor Assays /
                      Brain metastasis (Other) / Breast cancer (Other) /
                      Dihydrofolate reductase-mediated metastasis (Other) / Global
                      proteomics analysis (Other) / Lung metastasis (Other) /
                      Small extracellular vesicles and particles (sEVPs) (Other)},
      cin          = {A010 / W120 / B060 / W230 / HD01},
      ddc          = {570},
      cid          = {I:(DE-He78)A010-20160331 / I:(DE-He78)W120-20160331 /
                      I:(DE-He78)B060-20160331 / I:(DE-He78)W230-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40057730},
      pmc          = {pmc:PMC11889877},
      doi          = {10.1186/s12943-025-02235-8},
      url          = {https://inrepo02.dkfz.de/record/299575},
}