期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 7, 页码 918-932出版社
WILEY
DOI: 10.15252/emmm.201607354
关键词
clonal dynamics; pancreatic cancer; phenotypic plasticity; tumor-initiating cells
资金
- Deutsche Forschungsgemeinschaft [SFB873]
- NCT3.0 Precision Oncology Program [NCT3.0_2015.4 TransOnco]
- EU [TRANSCAN-2 ERA-NET]
- German Cancer Aid (Colon-Resist-Net)
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 longterm 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 in vivo 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.
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