Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer
A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2017
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| In: |
Journal of experimental medicine
Year: 2017, Jahrgang: 214, Heft: 7, Pages: 2073-2088 |
| ISSN: | 1540-9538 |
| DOI: | 10.1084/jem.20162017 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1084/jem.20162017 Verlag, kostenfrei, Volltext: http://jem.rupress.org/content/214/7/2073 
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| Verfasserangaben: | Klara M. Giessler, Kortine Kleinheinz, Daniel Huebschmann, Gnana Prakash Balasubramanian, Taronish D. Dubash, Sebastian M. Dieter, Christine Siegl, Friederike Herbst, Sarah Weber, Christopher M. Hoffmann, Raffaele Fronza, Ivo Buchhalter, Nagarajan Paramasivam, Roland Eils, Manfred Schmidt, Christof von Kalle, Martin Schneider, Alexis Ulrich, Claudia Scholl, Stefan Fröhling, Wilko Weichert, Benedikt Brors, Matthias Schlesner, Claudia R. Ball and Hanno Glimm |
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| 245 | 1 | 0 | |a Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer |c Klara M. Giessler, Kortine Kleinheinz, Daniel Huebschmann, Gnana Prakash Balasubramanian, Taronish D. Dubash, Sebastian M. Dieter, Christine Siegl, Friederike Herbst, Sarah Weber, Christopher M. Hoffmann, Raffaele Fronza, Ivo Buchhalter, Nagarajan Paramasivam, Roland Eils, Manfred Schmidt, Christof von Kalle, Martin Schneider, Alexis Ulrich, Claudia Scholl, Stefan Fröhling, Wilko Weichert, Benedikt Brors, Matthias Schlesner, Claudia R. Ball and Hanno Glimm |
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| 520 | |a A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample. Long-term growth in serial xenografts and spheroids was driven by multiple genomic subclones with profoundly differing growth dynamics and hence different quantitative contributions over time. Strikingly, genetic barcoding demonstrated stable functional heterogeneity of CRC TcICs during serial xenografting despite near-complete changes in genomic subclone contribution. This demonstrates that functional heterogeneity is, at least frequently, present within genomic subclones and independent of mutational subclone differences. | ||
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