Ball Claudia R, Oppel Felix, Ehrenberg Karl Roland, Dubash Taronish D, Dieter Sebastian M, Hoffmann Christopher M, Abel Ulrich, Herbst Friederike, Koch Moritz, Werner Jens, Bergmann Frank, Ishaque Naveed, Schmidt Manfred, von Kalle Christof, Scholl Claudia, Fröhling Stefan, Brors Benedikt, Weichert Wilko, Weitz Jürgen, Glimm Hanno
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
EMBO Mol Med. 2017 Jul;9(7):918-932. doi: 10.15252/emmm.201607354.
Although tumor-initiating cell (TIC) self-renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long-term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations. An unexpected functional and phenotypic plasticity of pancreatic TICs underlies the recruitment of inactive TIC clones in serial xenografts. The observed clonal succession of TIC activity in serial xenotransplantation is in stark contrast to the continuous activity of limited numbers of self-renewing TICs within a fixed cellular hierarchy observed in other epithelial cancers and emphasizes the need to target TIC activation, rather than a fixed TIC population, in PDAC.
尽管肿瘤起始细胞（TIC）的自我更新被认为在人类胰腺腺癌（PDAC）的进展和转移形成中至关重要，但PDAC肿瘤内TIC的克隆动态仍不清楚。在此，我们表明，在连续异种移植中，PDAC的长期进展是由一系列短暂活跃的TIC驱动的，这些TIC在时间上受限的爆发中产生肿瘤细胞。对单个基因标记的TIC进行克隆追踪发现，单个肿瘤是由不同的TIC集产生的，后续异种移植代之间的重叠非常少。胰腺TIC出人意料的功能和表型可塑性是连续异种移植中无活性TIC克隆募集的基础。在连续异种移植中观察到的TIC活性的克隆演替与在其他上皮癌中观察到的固定细胞层次结构中有限数量的自我更新TIC的持续活性形成鲜明对比，并强调在PDAC中靶向TIC激活而非固定的TIC群体的必要性。
