Guetter, Severin and Koenig, Courtney and Koerkel-Qu, Huiqin and Markiewicz, Aleksandra and Scheitler, Sebastian and Katzer, Marie and Berneburg, Mark and Renner, Philipp and Cucuruz, Beatrix and Guttenberger, Leonhard and Naimer, Veronika and Weidele, Kathrin and Treitschke, Steffi and Werno, Christian and Jaser, Hanna and Bargmann, Tonia and Braun, Armin and Weber, Florian and Evert, Katja and Rochwarger, Alexander and Schuerch, Christian M. and Limm, Katharina and Oefner, Peter J. and Rachel, Reinhard and Baumann, Felix and Warfsmann, Jens and Schmidleithner, Lisa and Guetter, Kathrin and Mohammadi, Parvaneh and Ulmer, Anja and Haferkamp, Sebastian and Klein, Christoph A. and Werner-Klein, Melanie (2025) MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization. NATURE CANCER, 6 (6). ISSN , 2662-1347
Full text not available from this repository. (Request a copy)Abstract
To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I-III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-gamma exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.
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