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

Abstract

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 TIC s 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 TIC s producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TIC s revealed that individual tumors are generated by distinct sets of TIC s with very little overlap between subsequent xenograft generations. An unexpected functional and phenotypic plasticity of pancreatic TIC s 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 TIC s 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 .