Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts Journal Article


Authors: Kuiken, H. J.; Dhakal, S.; Selfors, L. M.; Friend, C. M.; Zhang, T.; Callari, M.; Schackmann, R. C. J.; Gray, G. K.; Crowdis, J.; Bhang, H. E. C.; Baslan, T.; Stegmeier, F.; Gygi, S. P.; Caldas, C.; Brugge, J. S.
Article Title: Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts
Abstract: Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived from a single triple-negative breast cancer cell line, including copy number analysis, whole-exome and RNA sequencing, proteome analysis, and barcode analysis of clonal dynamics, as well as functional assays. The SCPs were found to have multiple unique genetic alterations and displayed significant variation in anchorage independent growth and tumor forming ability. Analyses of clonal dynamics in SCP mixtures using DNA barcode technology revealed selection for distinct clonal populations in different in vitro and in vivo environmental contexts, demonstrating that in vitro propagation of cancer cell lines using different culture conditions can contribute to the establishment of unique strains. These analyses also revealed strong enrichment of a single SCP during the development of xenograft tumors in immune-compromised mice. This SCP displayed attenuated interferon signaling in vivo and reduced sensitivity to the antiproliferative effects of type I interferons. Reduction in interferon signaling was found to provide a selective advantage within the xenograft microenvironment specifically. In concordance with the previously described role of interferon signaling as tumor suppressor, these findings suggest that similar selective pressures may be operative in human cancer and patient-derived xenograft models. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Journal Title: Oncogene
Volume: 41
Issue: 1
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2022-01-03
Start Page: 112
End Page: 124
Language: English
DOI: 10.1038/s41388-021-02075-y
PUBMED: 34703030
PROVIDER: scopus
PMCID: PMC8727509
DOI/URL:
Notes: Article -- Export Date: 1 February 2022 -- Source: Scopus
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  1. Timour Baslan
    46 Baslan