Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy

Funding: German Research Foundation DFG (SFB 873; subproject B08) (T.S. and A.M.-C); Heidelberg Graduate School (T.L.).We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structured by the expression level of a gene that controls cell proliferation and chemoresistance. In order to obtain an analytical description of evolutionary dynamics, we formally derive a deterministic continuum counterpart of this discrete model, which is given by a nonlocal parabolic equation for the cell population density function. Integrating computational simulations of the individual-based model with analysis of the corresponding continuum model, we perform a complete exploration of the model parameter space. We show that harsher environmental conditions and higher probabilities of spontaneous epimutation can lead to more effective chemotherapy, and we demonstrate the existence of an inverse relationship between the efficacy of the epigenetic drug and the probability of spontaneous epimutation. Taken together, the outcomes of the model provide theoretical ground for the development of anticancer protocols that use lower concentrations of chemotherapeutic agents in combination with epigenetic drugs capable of promoting the re-expression of epigenetically regulated genes.PostprintPeer reviewe

The value of plantation forests for plant, invertebrate and bird diversity and the potential for cross-taxon surrogacy

As the area of plantation forest expands worldwide and natural, unmanaged forests decline there is much interest in the potential for planted forests to provide habitat for biodiversity. In regions where little semi-natural woodland remains, the biodiversity supported by forest plantations, typically non-native conifers, may be particularly important. Few studies provide detailed comparisons between the species diversity of native woodlands which are being depleted and non-native plantation forests, which are now expanding, based on data collected from multiple taxa in the same study sites. Here we compare the species diversity and community composition of plants, invertebrates and birds in Sitka spruce- (Picea sitchensis-) dominated and Norway spruce- (Picea abies-) dominated plantations, which have expanded significantly in recent decades in the study area in Ireland, with that of oak- and ash-dominated semi-natural woodlands in the same area. The results show that species richness in spruce plantations can be as high as semi-natural woodlands, but that the two forest types support different assemblages of species. In areas where non-native conifer plantations are the principle forest type, their role in the provision of habitat for biodiversity conservation should not be overlooked. Appropriate management should target the introduction of semi-natural woodland characteristics, and on the extension of existing semi-natural woodlands to maintain and enhance forest species diversity. Our data show that although some relatively easily surveyed groups, such as vascular plants and birds, were congruent with many of the other taxa when looking across all study sites, the similarities in response were not strong enough to warrant use of these taxa as surrogates of the others. In order to capture a wide range of biotic variation, assessments of forest biodiversity should either encompass several taxonomic groups, or rely on the use of indicators of diversity that are not species based