Non-Darwinian dynamics in therapy-induced cancer drug resistance

Pisco, Angela Oliveira; Brock, Amy; Zhou, Joseph; Moor, Andreas E.; Mojtahedi, Mitra; Jackson, Dean A.; Huang, Sui

doi:10.1038/ncomms3467

Cited by 277 publications

(360 citation statements)

References 68 publications

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“…The wide distribution of single cells in a cancer cell attractor is expected to produce the constellation that some cells in the population are resistant to a given drug at a certain time point but not at another time point when they have shifted position in the state space (26,(32)(33)(34)(35)(36). When the selective pressure of treatment is released, the original population can be reestablished by these few temporarily resistant edge cells.…”

Section: Discussionmentioning

confidence: 99%

“…These cells could survive at a new state space position (attractor), because the new attractor affords compensatory functions as part of the associated gene expression program, a typically stem-like phenotype that is inherent in the GRN (17,26,30,31). These compensatory mechanisms are probably those that should be sought out and targeted when conventional approaches have failed (32).…”

Section: Discussionmentioning

confidence: 99%

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Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape

Wennborg

Aurell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker-Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer.cancer cell attractor | cell heterogeneity | edge cells | gene regulatory network | cell population dynamics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape

Wennborg

Aurell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

100

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show abstract

“…In order to address these questions, in [6] we proposed an Individual-Based (I-B) computational model [4,[7][8][9] and an Integro-Differential Equation (IDE) model [10][11][12] of the phenotype evolution observed in [1]. Such models can be used as in silico laboratories to test verbal hypotheses, and uncover mechanisms that underlie emergent features of cancer cell populations.…”

Section: Introductionmentioning

confidence: 99%

Emergence of cytotoxic resistance in cancer cell populations*

Lorenzi

Chisholm

Lorz

et al. 2015

ITM Web of Conferences

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Abstract. We formulate an individual-based model and an integro-differential model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

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“…Moreover, the silencing of tumour suppressor gene expression by promoter hypermethylation at CpG-rich islands is common among several human malignancies [6,7]. Epigenetic mechanisms have been implicated in acquired drug-tolerance of cancer cells during in vitro experiments [8][9][10]. They are also recognised as key drivers in the success of invasive clonal plant species [11].…”

Section: Introductionmentioning

confidence: 99%

Evolutionary dynamics of phenotype-structured populations: from individual-level mechanisms to population-level consequences

Chisholm

Lorenzi

Desvillettes

et al. 2016

Z. Angew. Math. Phys.

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Abstract. Epigenetic mechanisms are increasingly recognised as integral to the adaptation of species that face environmental changes. In particular, empirical work has provided important insights into the contribution of epigenetic mechanisms to the persistence of clonal species, from which a number of verbal explanations have emerged that are suited to logical testing by proof-of-concept mathematical models. Here, we present a stochastic agent-based model and a related deterministic integrodifferential equation model for the evolution of a phenotype-structured population composed of asexually-reproducing and competing organisms which are exposed to novel environmental conditions. This setting has relevance to the study of biological systems where colonising asexual populations must survive and rapidly adapt to hostile environments, like pathogenesis, invasion and tumour metastasis. We explore how evolution might proceed when epigenetic variation in gene expression can change the reproductive capacity of individuals within the population in the new environment. Simulations and analyses of our models clarify the conditions under which certain evolutionary paths are possible, and illustrate that whilst epigenetic mechanisms may facilitate adaptation in asexual species faced with environmental change, they can also lead to a type of "epigenetic load" and contribute to extinction. Moreover, our results offer a formal basis for the claim that constant environments favour individuals with low rates of stochastic phenotypic variation. Finally, our model provides a "proof of concept" of the verbal hypothesis that phenotypic stability is a key driver in rescuing the adaptive potential of an asexual lineage, and supports the notion that intense selection pressure can, to an extent, offset the deleterious effects of high phenotypic instability and biased epimutations, and steer an asexual population back from the brink of an evolutionary dead end.

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Non-Darwinian dynamics in therapy-induced cancer drug resistance

Cited by 277 publications

References 68 publications

Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape

Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape

Emergence of cytotoxic resistance in cancer cell populations*

Evolutionary dynamics of phenotype-structured populations: from individual-level mechanisms to population-level consequences

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