RT Journal Article
SR Electronic
T1 Cancer evolution simulation identifies possible principles underlying intratumor heterogeneity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 022806
DO 10.1101/022806
A1 Atsushi Niida
A1 Satoshi Ito
A1 Georg Tremmel
A1 Seiya Imoto
A1 Ryutaro Uchi
A1 Yusuke Takahashi
A1 Koshi Mimori
A1 Satoru Miyano
YR 2015
UL http://biorxiv.org/content/early/2015/07/17/022806.abstract
AB Cancer arises from accumulation of somatic mutations and accompanying evolutionary selection for growth advantage. During the evolutionary process, an ancestor clone branches into multiple clones, yielding intratumor heterogeneity. However, principles underlying intratumor heterogeneity have been poorly un-derstood. Here, to explore the principles, we built a cellular automaton model, termed the BEP model, which can reproduce the branching cancer evolution in silico. We then extensively searched for conditions leading to high intratu-mor heterogeneity by performing simulations with various parameter settings on a supercomputer. Our result suggests that multiple driver genes of moderate strength can shape subclonal structures by positive natural selection. Moreover, we found that high mutation rate and a stem cell hierarchy can contribute to extremely high intratumor heterogeneity, which is characterized by fractal patterns, through neutral evolution. Collectively, This study identified the possible principles underlying intratumor heterogeneity, which provide novel insights into the origin of cancer robustness and evolvability.