A unified simulation model for understanding the diversity of cancer evolution

Abstract

Because cancer evolution underlies the therapeutic difficulties of cancer, it is clinically important to understand the evolutionary dynamics of cancer. Thus far, a number of evolutionary processes have been proposed to be working in cancer evolution. However, there exists no simulation model that can describe the different evolutionary processes in a unified manner. In this study, we constructed a unified simulation model for describing the different evolutionary processes and performed sensitivity analysis on the model to determine the conditions in which cancer growth is driven by each of the different evolutionary processes. Our sensitivity analysis has successfully provided a series of novel insights into the evolutionary dynamics of cancer. For example, we found that, while a high neutral mutation rate shapes neutral intratumor heterogeneity (ITH) characterized by a fractal-like pattern, a stem cell hierarchy can also contribute to shaping neutral ITH by apparently increasing the mutation rate. Although It has been reported that the evolutionary principle shaping ITH shifts from selection to accumulation of neutral mutations during colorectal tumorigenesis, our simulation revealed the possibility that this evolutionary shift is triggered by drastic evolutionary events that occur in a short time and confer a marked fitness increase on one or a few cells. This result helps us understand that each process works not separately but simultaneously and continuously as a series of phases of cancer evolution. Collectively, this study serves as a basis to understand in greater depth the diversity of cancer evolution.

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“…The malignant stem cells adapt to the 2 of 15 microenvironment in the bone marrow. If the malignant stem cells are sufficiently fit, they may outcompete the healthy stem cells and acquire further malignant mutations-e.g., becoming therapeutic-resistant and metastasizing [9]. The risk of the acquisition of additional mutations is proportional to the number of malignant cells.…”

Modeling colorectal cancer evolution

“…The clinical significance of different ITH properties remains unclear but has been proposed to be associated with clinical disease course [ 10 ]. A few studies employing mathematical modeling have also been performed to understand the mechanisms generating ITHs with different evolutionary properties [ 14 , 15 ].…”

“…To examine this hypothesis, we employed mathematical modeling [ 14 ]. We modified the BEP model to reproduce punctuated evolution.…”

“…Note that the driver mutation exists as subclonal mutations at the beginning but shifts to clonal mutations, as the clone acquiring the explosive driver mutation expands. This image was obtained by modifying a figure which originally appeared in our previous work [ 14 ] …”

“…The neutral evolution phase following punctuated evolution is also consistent with the recently proposed Big Bang model [ 10 ], where a tumor predominantly grows as a single expansion without selective sweep. It should also be noted that our model of the evolutionary shift from Darwinian selection to neutral evolution might be a simplified view; different evolutionary processes actually work not separately but simultaneously and continuously as a series of phases of cancer evolution, which is discussed in our previous paper [ 14 ].…”