The effect of spatial fitness heterogeneity on fixation probability
Kaveh K, McAvoy A, Nowak MA. The effect of spatial fitness heterogeneity on fixation probability. Forthcoming.Abstract


Environmental variation is featured widely in nature, yet mathematical investigations into evolutionary processes often assume a mini- mal amount of heterogeneity. Two traits might be distinguished by their reproductive fitness, but, in models, this fitness difference is frequently the only property that differentiates a mutant type from the wild type. Here, we study evolution in heterogeneous environments. For two competing traits, A and B, we allow reproductive fitness to depend on both the trait and the location of the individual possessing it. We show that, in large populations, A is favored relative to B if and only the expected fitness of a randomly-placed A-individual exceeds that of a randomly-placed B-individual. Furthermore, fitness heterogeneity of the wild type (B) does not affect the fixation probability of the mutant type (A), but spatial variation in mutant fitness always acts as a suppressor of selection. In fact, sufficiently strong heterogeneity in mutant fitness can completely offset the effects of natural selection. In random environments in which fitness values are determined by a probability distribution, we calculate the asymptotic distribution of the fixation probability of a single, randomly-placed mutant. This result is similar to the central limit theorem and it reflects how uncertainty in fixation probability correlates with population size and uncertainty in reproductive rates. 


Stem cell evolutionary dynamics of differentiation and plasticity
Kaveh K. Stem cell evolutionary dynamics of differentiation and plasticity. Cur. Stem Cell Rep. [Internet]. 2017. Publisher's VersionAbstract
The role of tissue-specific stem cells, differentiation, and the resulting phenotypic heterogeneity in evolution of new mutations has attracted the interest of theoreticians and experimentalists. In the current paper, we first summarize the literature on population dynamics of stem cell and differentiated populations, in the absence of somatic mutations, with focus on applications to cancer therapeutics. We then review recent experimental and theoretical works on the evolutionary dynamics of stem cells and their progenitors in the presence of rare somatic mutation.
Combination therapeutics of Nilotinib and radiation in Acute Lymphoblastic Leukemia as an effective method against drug-resistance.
Kaveh K, Takahashi Y, Farrar MA, Storme G, Guido M, Piepenburg J, Penning J, Foo J, Leder KZ, Hui SK. Combination therapeutics of Nilotinib and radiation in Acute Lymphoblastic Leukemia as an effective method against drug-resistance. PLoS Computational Biology. 2017.Abstract


Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcom, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additonally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy. 


Phenotypic heterogeneity in modeling cancer evolution
Mahdipour A, Kaveh K, Kohandel M, Sivaloganathan S. Phenotypic heterogeneity in modeling cancer evolution. PLoS one. 2017.Abstract

The unwelcome evolution of malignancy during cancer progression emerges through a selection process in a complex heterogeneous population structure. In the present work, we investigate evolutionary dynamics in a phenotypically heterogeneous population of stem cells (SCs) and their associated progenitors. The fate of a malignant mutation is determined not only by overall stem cell and differentiated cell growth rates but also differentiation and dedifferentiation rates. We investigate the effect of such a complex population structure on the evolution of malignant mutations. We derive exact analytic results for the fixation probability of a mutant arising in each of the subpopulations. The analytic results are in almost perfect agreement with the numerical simulations. Moreover, a condition for evolutionary advantage of a mutant cell versus the wild type population is given in the present study. We also show that microenvironment-induced plasticity in invading mutants leads to more aggressive mutants with higher fixation probability. Our model predicts that decreasing polarity between stem and differentiated cells turnover would raise the survivability of non-plastic mutants; while it would suppress the development of malignancy for plastic mutants. We discuss our model in the context of colorectal/intestinal cancer (at the epithelium). This novel mathematical framework can be applied more generally to a variety of problems concerning selection in heterogeneous populations, in other contexts such as population genetics, and ecology.

Games of multicellularity
Kaveh K, Veller C, Nowak MA. Games of multicellularity. Journal of Theoretical Biology. 2016;403 :143-158.Abstract

Evolutionary game dynamics are often studied in the context of different population structures. Here we propose a new population structure that is inspired by simple multicellular life forms. In our model, cells reproduce but can stay together after reproduction. They reach complexes of a certain size, n, before producing single cells again. The cells within a complex derive payoff from an evolutionary game by interacting with each other. The reproductive rate of cells is proportional to their payoff. We consider all two-strategy games. We study deterministic evolutionary dynamics with mutations, and derive exact conditions for selection to favor one strategy over another. Our main result has the same symmetry as the well-known sigma condition, which has been proven for stochastic game dynamics and weak selection. For a maximum complex size of n  =2 our result holds for any intensity of selection. For n≥3 it holds for weak selection. As specific examples we study the prisoner's dilemma and hawk-dove games. Our model advances theoretical work on multicellularity by allowing for frequency-dependent interactions within groups.

Modeling age-dependent radiation-induced second cancer risks and estimation of mutation rate: an evolutionary approach
Kaveh K, Manem VSK, Kohandel M, Sivaloganathan S. Modeling age-dependent radiation-induced second cancer risks and estimation of mutation rate: an evolutionary approach. Radiat Environ Biophys. 2015. modeling_age-dependent_radiation-induced_second_cancer_risks_and_estimation_of_mutation_rate_an_evolutionary_approach_01.pdf
Modeling Invasion Dynamics with Spatial Random-Fitness Due to Micro-Environment
Manem VSK, Kaveh K, Kohandel M, Sivaloganathan S. Modeling Invasion Dynamics with Spatial Random-Fitness Due to Micro-Environment. PLoS one. 2015;10 (10) :e0140234.Abstract

Numerous experimental studies have demonstrated that the microenvironment is a key regulator influencing the proliferative and migrative potentials of species. Spatial and temporal disturbances lead to adverse and hazardous microenvironments for cellular systems that is reflected in the phenotypic heterogeneity within the system. In this paper, we study the effect of microenvironment on the invasive capability of species, or mutants, on structured grids (in particular, square lattices) under the influence of site-dependent random proliferation in addition to a migration potential. We discuss both continuous and discrete fitness distributions. Our results suggest that the invasion probability is negatively correlated with the variance of fitness distribution of mutants (for both advantageous and neutral mutants) in the absence of migration of both types of cells. A similar behaviour is observed even in the presence of a random fitness distribution of host cells in the system with neutral fitness rate. In the case of a bimodal distribution, we observe zero invasion probability until the system reaches a (specific) proportion of advantageous phenotypes. Also, we find that the migrative potential amplifies the invasion probability as the variance of fitness of mutants increases in the system, which is the exact opposite in the absence of migration. Our computational framework captures the harsh microenvironmental conditions through quenched random fitness distributions and migration of cells, and our analysis shows that they play an important role in the invasion dynamics of several biological systems such as bacterial micro-habitats, epithelial dysplasia, and metastasis. We believe that our results may lead to more experimental studies, which can in turn provide further insights into the role and impact of heterogeneous environments on invasion dynamics.

Replicator dynamics of cancer stem cell: Selection in the presence of differentiation and plasticity
Kaveh K, Kohandel M, Sivaloganathan S. Replicator dynamics of cancer stem cell: Selection in the presence of differentiation and plasticity. Mathematical biosciences. 2015;272 :64-75.Abstract


The cancer stem cell hypothesis has evolved into one of the most important paradigms in cancer research. According to cancer stem cell hypothesis, somatic mutations in a subpopulation of cells can transform them into cancer stem cells with the unique potential of tumour initiation. Stem cells have the potential to pro- duce lineages of non-stem cell populations (differentiated cells) via a ubiquitous hierarchal division scheme. Differentiation of a stem cell into (partially) differentiated cells can happen either symmetrically or asym- metrically. The selection dynamics of a mutant cancer stem cell should be investigated in the light of a stem cell proliferation hierarchy and presence of a non-stem cell population. By constructing a three-compartment Moran-type model composed of normal stem cells, mutant (cancer) stem cells and differentiated cells, we de- rive the replicator dynamics of stem cell frequencies where asymmetric differentiation and differentiated cell death rates are included in the model. We determine how these new factors change the conditions for a suc- cessful mutant invasion and discuss the variation on the steady state fraction of the population as different model parameters are changed. By including the phenotypic plasticity/dedifferentiation, in which a progeni- tor/differentiated cell can transform back into a cancer stem cell, we show that the effective fitness of mutant stem cells is not only determined by their proliferation and death rates but also according to their dediffer- entiation potential. By numerically solving the model we derive the phase diagram of the advantageous and disadvantageous phases of cancer stem cells in the space of proliferation and dedifferentiation potentials. The result shows that at high enough dedifferentiation rates even a previously disadvantageous mutant can take over the population of normal stem cells. This observation has implications in different areas of cancer research including experimental observations that imply metastatic cancer stem cell types might have lower proliferation potential than other stem cell phenotypes while showing much more phenotypic plasticity and can undergo clonal expansion. 


The duality of spatial death–birth and birth–death processes and limitations of the isothermal theorem
Kaveh K, Komarova NL, Kohandel M. The duality of spatial death–birth and birth–death processes and limitations of the isothermal theorem. Royal Society open science. 2015;2 :140465.Abstract

Evolutionary models on graphs, as an extension of the Moran process, have two major implementations: birth–death (BD) models (or the invasion process) and death–birth (DB) models (or voter models). The isothermal theorem states that the fixation probability of mutants in a large group of graph structures (known as isothermal graphs, which include regular graphs) coincides with that for the mixed population. This result has been proved by Lieberman et al. (2005 Nature 433, 312–316. (doi:10.1038/nature03204)) in the case of BD processes, where mutants differ from the wild-types by their birth rate (and not by their death rate). In this paper, we discuss to what extent the isothermal theorem can be formulated for DB processes, proving that it only holds for mutants that differ from the wild-type by their death rate (and not by their birth rate). For more general BD and DB processes with arbitrary birth and death rates of mutants, we show that the fixation probabilities of mutants are different from those obtained in the mass-action populations. We focus on spatial lattices and show that the difference between BD and DB processes on one- and two-dimensional lattices is non-small even for large population sizes. We support these results with a generating function approach that can be generalized to arbitrary graph structures. Finally, we discuss several biological applications of the results.

Stochastic model for tumor control probability: effects of cell cycle and (a) symmetric proliferation
Dhawan A, Kaveh K, Kohandel M, Sivaloganathan S. Stochastic model for tumor control probability: effects of cell cycle and (a) symmetric proliferation. Theoretical Biology and Medical Modeling. 2014;11 (1) :1.Abstract


Background: Estimatingtherequireddoseinradiotherapyisofcrucialimportance since the administrated dose should be sufficient to eradicate the tumor and at the same time should inflict minimal damage on normal cells. The probability that a given dose and schedule of ionizing radiation eradicates all the tumor cells in a given tissue is called the tumor control probability (TCP), and is often used to compare various treatment strategies used in radiation therapy.

Method: Inthispaper,weaimtoinvestigatetheeffectsofincludingcell-cyclephase on the TCP by analyzing a stochastic model of a tumor comprised of actively dividing cells and quiescent cells with different radiation sensitivities. Moreover, we use a novel numerical approach based on the method of characteristics for partial differential equations, validated by the Gillespie algorithm, to compute the TCP as a function of time.

Results: Wederiveanexactphase-diagramforthesteady-stateTCPofthemodeland show that at high, clinically-relevant doses of radiation, the distinction between active and quiescent tumor cells (i.e. accounting for cell-cycle effects) becomes of negligible importance in terms of its effect on the TCP curve. However, for very low doses of radiation, these proportions become significant determinants of the TCP. We also present the results of TCP as a function of time for different values of asymmetric division factor.

Conclusion: Weobservethatourresultsdifferfromtheresultsintheliteratureusing similar existing models, even though similar parameters values are used, and the reasons for this are discussed. 


Birefringent breakup of Dirac fermions on a square optical lattice
Kennett MP, Komeilizadeh N, Kaveh K, Smith P. Birefringent breakup of Dirac fermions on a square optical lattice. Physical Review A. 2010;83 (8) :053636.Abstract

We introduce a lattice model for fermions in a spatially periodic magnetic field that also has spatially periodic hopping amplitudes. We discuss how this model might be realized with cold atoms in an artificial magnetic field on a square optical lattice. When there is an average flux of half a flux quantum per plaquette, the spectrum of low-energy excitations can be described by massless Dirac fermions in which the usually doubly degenerate Dirac cones split into cones with different “speeds of light.” These gapless birefringent Dirac fermions arise because of broken chiral symmetry in the kinetic energy term of the effective low-energy Hamiltonian. We characterize the effects of various perturbations to the low-energy spectrum, including staggered potentials, interactions, and domain-wall topological defects.