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Succession of transiently active tumor‐initiating cell clones in human pancreatic cancer xenografts

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 xenotranspla...

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Main Authors: Ball, Claudia R. (Author) , Oppel, Felix (Author) , Ehrenberg, Karl Roland (Author) , Dubash, Taronish Dorab (Author) , Dieter, Sebastian M. (Author) , Hoffmann, Christopher M. (Author) , Abel, Ulrich (Author) , Herbst, Friederike (Author) , Koch, Moritz (Author) , Werner, Jens (Author) , Bergmann, Frank (Author) , Schmidt, Manfred (Author) , Kalle, Christof von (Author) , Scholl, Claudia (Author) , Fröhling, Stefan (Author) , Brors, Benedikt (Author) , Weichert, Wilko (Author) , Weitz, Jürgen (Author) , Glimm, Hanno (Author)
Format: Article (Journal)
Language:English
Published: 19 May 2017
In: EMBO molecular medicine
Year: 2017, Volume: 9, Issue: 7, Pages: 918-932
ISSN:1757-4684
DOI:10.15252/emmm.201607354
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.15252/emmm.201607354
Verlag, kostenfrei, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494525/
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Author Notes:Claudia R Ball, Felix Oppel, Karl Roland Ehrenberg, Taronish D Dubash, Sebastian M Dieter, Christopher M Hoffmann, Ulrich Abel, Friederike Herbst, Moritz Koch, Jens Werner, Frank Bergmann, Naveed Ishaque, Manfred Schmidt, Christof von Kalle, Claudia Scholl, Stefan Fröhling, Benedikt Brors, Wilko Weichert, Jürgen Weitz and Hanno Glimm

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520 |a 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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