Guetter Severin, König Courtney, Koerkel-Qu Huiqin, Markiewicz Aleksandra, Scheitler Sebastian, Katzer Marie, Berneburg Mark, Renner Philipp, Cucuruz Beatrix, Guttenberger Leonhard, Naimer Veronika, Weidele Kathrin, Treitschke Steffi, Werno Christian, Jaser Hanna, Bargmann Tonia, Braun Armin, Weber Florian, Evert Katja, Rochwarger Alexander, Schürch Christian M, Limm Katharina, Oefner Peter J, Rachel Reinhard, Baumann Felix, Warfsmann Jens, Schmidleithner Lisa, Guetter Kathrin, Mohammadi Parvaneh, Ulmer Anja, Haferkamp Sebastian, Klein Christoph A, Werner-Klein Melanie
Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany.
Department of Dermatology, University Medical Center Regensburg, Regensburg, Germany.
Nat Cancer. 2025 May 16. doi: 10.1038/s43018-025-00963-w.
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-γ 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.
为了研究驱动转移进展的早期、尚未完全了解的事件，我们在492例I - III期黑色素瘤患者的前哨淋巴结（SLN）活检中寻找最早可检测到的播散癌细胞（DCC），其也常被称为播散肿瘤细胞（DTC）。通过使用微操纵器辅助分离罕见的DCC、单细胞mRNA和DNA测序、索引免疫荧光成像共检测以及生存分析，我们将黑色素瘤相关硫酸软骨素蛋白聚糖（MCSP）黑色素瘤细胞鉴定为转移起始细胞（MFC）。我们发现进入SLN的DCC主要表现出一种短暂的表型，在CD8 T细胞触发的干扰素-γ暴露后，会去分化为神经嵴样表型。这伴随着携带免疫调节蛋白CD155和CD276但很少携带程序性细胞死亡蛋白1配体1的小细胞外囊泡（sEV）产量增加。这些sEV抑制CD8 T细胞增殖和功能，促进集落形成。靶向MCSP MFC或其免疫逃逸机制可能是通过预防转移表现来早期治愈黑色素瘤的关键。
