Modeling the evolutionary and differentiation dynamics of neoplastic progression

Cancer is an evolutionary system that results from the accumulation of somatic mutations, many of which are thought to increase somatic fitness of cells by allowing them to divide faster, die less frequently, or ignore the rules dictated by their environments. New mutations in individual cells within a neoplasm can create subclones of genetically identical cells all sharing a common ancestor, and these subclones can then compete with each other for limited resources. We consider somatic evolution in two contexts: the progression of normal cell populations to cancer cell populations, and the dynamics of evolution within cancer cell populations. Additionally, human tissues are subdivided into populations with varying levels of proliferative potential. In this context, stem cells are thought to divide symmetrically to replenish their numbers and asymmetrically to generate the transient cells which in turn generate the terminally differentiated cells that make up the bulk of the tissue and perform their tissue specific roles; transient cells can divide multiple times, becoming progressively more differentiated. This architecture of differentiation minimizes the accumulation of mutations; tissues in which disruptions to the forward-only architecture - through self-renewal, loss of differentiation, or dedifferentiation - are more likely to acquire mutations and become malignant. Here, we use modeling to explore the consequences of differentiation architecture on evolution in cancer