TY  - JOUR
AU  - Giessler, Klara
AU  - Kleinheinz, Kortine
AU  - Huebschmann, Daniel
AU  - Balasubramanian, Gnana Prakash
AU  - Dubash, Taronish Dorab
AU  - Dieter, Sebastian M
AU  - Siegl, Christine
AU  - Herbst, Friederike
AU  - Weber, Sarah
AU  - Hoffmann, Christopher M
AU  - Fronza, Raffaele
AU  - Buchhalter, Ivo
AU  - Paramasivam, Nagarajan
AU  - Eils, Roland
AU  - Schmidt, Manfred
AU  - von Kalle, Christof
AU  - Schneider, Martin
AU  - Ulrich, Alexis
AU  - Scholl, Claudia
AU  - Fröhling, Stefan
AU  - Weichert, Wilko
AU  - Brors, Benedikt
AU  - Schlesner, Matthias
AU  - Ball, Claudia R
AU  - Glimm, Hanno
TI  - Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer.
JO  - Journal of experimental medicine
VL  - 214
IS  - 7
SN  - 1540-9538
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DKFZ-2017-01357
SP  - 2073 - 2088
PY  - 2017
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:28572216
C2  - pmc:PMC5502434
DO  - DOI:10.1084/jem.20162017
UR  - https://inrepo02.dkfz.de/record/125202
ER  -