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EMBO Mol Med. 2017 Jul;9(7):918-932. doi: 10.15252/emmm.201607354.

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

Author information

1
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
3
German Cancer Consortium (DKTK), University of Heidelberg, Heidelberg, Germany.
4
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
5
Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Dresden, Germany.
6
Department of Surgery, University of Munich, Munich, Germany.
7
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
8
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany.
10
Heidelberg University Hospital, Heidelberg, Germany.
11
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany hanno.glimm@nct-heidelberg.de.

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.

KEYWORDS:

clonal dynamics; pancreatic cancer; phenotypic plasticity; tumor‐initiating cells

PMID:
28526679
PMCID:
PMC5494525
DOI:
10.15252/emmm.201607354
[Indexed for MEDLINE]
Free PMC Article

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