Modeling evolutionary dynamics of epigenetic mutations in hierarchically organized tumors

The cancer stem cell (CSC) concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-)hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model.
Author Summary Cancer is in essence a genetic disease that leads to uncontrolled cell proliferation, invasion and metastasis. The cancer stem cell (CSC) hypothesis states that tumors are not just a mass of uniform malignant cells but they are hierarchically organized, like normal tissues. At the top of such a hierarchy are cancer stem cells that fuel tumor growth in the long run, whereas the majority of other cells are able to divide only a few times. The experiments that support the CSC hypothesis are often criticized as being difficult to interpret. A novel approach to test the CSC paradigm is to integrate mathematical modeling with DNA variation data that carry the phylogenetic history of cells. We have developed a model that simulates the occurrence of such changes under both the CSC hypothesis and the classical, purely stochastic scenario. We found that although a CSC-driven tumor has a smaller number of tumorigenic cells, it triggers more malignant properties such as invasive growth, heterogeneity and evolutionary escape from peaks in the fitness landscape. These properties, that are unique to the CSC model, are enhanced even further when a treatment is applied to the tumor.