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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Claudia R. Ball - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Research Center (DKFZ) (Author)
  • Felix Oppel - , German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) Dresden (Author)
  • Karl Roland Ehrenberg - , German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Taronish D. Dubash - , German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Sebastian M. Dieter - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Christopher M. Hoffmann - , German Cancer Research Center (DKFZ) (Author)
  • Ulrich Abel - , German Cancer Research Center (DKFZ) (Author)
  • Friederike Herbst - , German Cancer Research Center (DKFZ) (Author)
  • Moritz Koch - , Heidelberg University , University Hospital Carl Gustav Carus Dresden, Department of Visceral, Thoracic and Vascular Surgery (Author)
  • Jens Werner - , Heidelberg University , Ludwig Maximilian University of Munich (Author)
  • Frank Bergmann - , Heidelberg University  (Author)
  • Naveed Ishaque - , German Cancer Research Center (DKFZ) (Author)
  • Manfred Schmidt - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Christof von Kalle - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Claudia Scholl - , German Cancer Research Center (DKFZ) (Author)
  • Stefan Fröhling - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Benedikt Brors - , German Cancer Research Center (DKFZ) (Author)
  • Wilko Weichert - , Heidelberg University  (Author)
  • Jürgen Weitz - , Department of Visceral, Thoracic and Vascular Surgery, Heidelberg University , University Hospital Carl Gustav Carus Dresden (Author)
  • Hanno Glimm - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Research Center (DKFZ), Heidelberg University  (Author)

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.

Details

Original languageEnglish
Pages (from-to)918-932
Number of pages15
JournalEMBO molecular medicine
Volume9
Issue number7
Publication statusPublished - Jul 2017
Peer-reviewedYes

External IDs

PubMed 28526679

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • clonal dynamics, pancreatic cancer, phenotypic plasticity, tumor-initiating cells