Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts
Claudia R. Ball,Felix Oppel,Karl Roland Ehrenberg,Taronish D. Dubash,Sebastian M. Dieter,Sebastian M. Dieter,Christopher M. Hoffmann,Ulrich Abel,Friederike Herbst,Moritz Koch,Jens Werner,Jens Werner,Frank Bergmann,Naveed Ishaque,Manfred G. Schmidt,Manfred G. Schmidt,Christof von Kalle,Christof von Kalle,Claudia Scholl,Stefan Frohling,Stefan Frohling,Benedikt Brors,Wilko Weichert,Wilko Weichert,Jürgen Weitz,Hanno Glimm,Hanno Glimm +26 more
TL;DR: It is shown 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, and emphasizes the need to target TIC activation, rather than a fixed TIC population, in PDAC.
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Abstract: 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 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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