Intratumor Heterogeneity in Evolutionary Models of Tumor Progression

Abstract

With rare exceptions, human tumors arise from single cells that have accumulated the necessary number and types of heritable alterations. Each such cell leads to dysregulated growth and eventually the formation of a tumor. Despite their monoclonal origin, at the time of diagnosis most tumors show a striking amount of intratumor heterogeneity in all measurable phenotypes; such heterogeneity has implications for diagnosis, treatment efficacy, and the identification of drug targets. An understanding of the extent and evolution of intratumor heterogeneity is therefore of direct clinical importance. In this article, we investigate the evolutionary dynamics of heterogeneity arising during exponential expansion of a tumor cell population, in which heritable alterations confer random fitness changes to cells. We obtain analytical estimates for the extent of heterogeneity and quantify the effects of system parameters on this tumor trait. Our work contributes to a mathematical understanding of intratumor heterogeneity and is also applicable to organisms like bacteria, agricultural pests, and other microbes.H UMAN cancers frequently display substantial intratumor heterogeneity in genotype, gene expression, cellular morphology, metabolic activity, motility, and behaviors such as proliferation rate, antigen expression, drug response, and metastatic potential (Fidler and Hart

Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria

“…In turn, the existence of an upper limit to diversity when mutations are advantageous (r . 2) was predicted by Durrett et al (2011) in their analysis of exponentially expanding tumor cell populations. Interestingly, this observation contrasts with that of Pennings and Hermisson (2006) in the context of soft selective sweeps, where diversity was found to follow Ewens' sampling formula.…”

“…This probability is usually referred to in the ecological literature as Simpson's index (Gregorius and Gillet 2008), and it is commonly applied to describe intratumor heterogeneity in the field of cancer evolution (Maley et al 2006;Durrett et al 2011;Iwasa and Michor 2011;Gatenby et al 2014) [note that this metric is conceptually similar to the probability of identityby-descent used in classical population genetics (Malécot and Blaringhem 1948)]. When t = 0, Simpson's index is not defined, since there is only one mutant in the whole population.…”

“…The topic of genetic diversity in asexuals has received renewed attention during the last decade, spurred by the observation of clonal interference in microbial experimental evolution (de Visser and Rozen 2006;Kosheleva and Desai 2013) and by the recognition of intratumor diversity as a predictor of cancer outcomes (Maley et al 2006;Durrett et al 2011). Here we focus on the relevant but still unexplored case of the diversity at antibiotic-resistance loci within a subpopulation of resistant cells.…”

“…Since diagnostic biopsies typically sample only a small portion of the lesion, inferences about total diversity rely heavily on the accuracy of available population genetic models (Beerenwinkel et al 2015). The theoretical literature has largely focused on the dynamics of diversity during the successive sweeps of beneficial "driver" mutations, generally neglecting neutral and deleterious variation not linked to the drivers (Bozic et al 2010;Durrett et al 2011;Iwasa and Michor 2011). This nonadaptive variation can become important, however, in the event of a sudden lethal selection, such as in the case of chemoresistance, often associated with a fitness cost (Liang et al 2008;Silva et al 2012).…”

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

“…Since neoangiogenesis was identified as a fundamental factor in tumor growth, many antiangiogenic agents have been developed 1, 2, 3, 4, 5, 6. Despite an early expectation that these therapeutic agents would successfully increase survival time in patients with solid tumors, validation of meaningful survival benefits has failed in a considerable number of clinical trials.…”