Turning ecology and evolution against cancer

Korolev, Kirill S.; Xavier, João B.; Gore, Jeff

doi:10.1038/nrc3712

Cited by 278 publications

(294 citation statements)

References 134 publications

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“…This could suggest that tumour growth in some instances benefit from maintaining a balance between subpopulations of neoplastic cells with different genotypes. Whether this is a sign of tumour cell interdependence for optimal growth remains to be explored 32 . On the other hand, there was also evidence of clonal evolution followed by expansion of a subclone up to a point where genetic diversity was largely eliminated (Case 4; Fig.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

et al. 2015

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Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P ¼ 0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

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Section: Discussionmentioning

confidence: 99%

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

et al. 2015

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“…For a system with alternative stable states (3,4), pressure on an environmental driver pushes the system closer to a tipping point (5,6). Once the driver crosses a certain threshold, the system goes through a critical transition and shifts to a different state [e.g., the malignant behavior of cancer (1), the collapse of pollinator populations (7), or a large-scale mass extinction (8,9)]. …”

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confidence: 99%

“…Microenvironmental cues such as growth factors and drug concentrations control the progression of cancer cells (1). Parasites, insecticides, and habitat destruction have all been blamed for the rapid decline of honey bee colonies in the North America (2).…”

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confidence: 99%

Relation between stability and resilience determines the performance of early warning signals under different environmental drivers

Dai

Korolev

Gore

2015

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

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Shifting patterns of temporal fluctuations have been found to signal critical transitions in a variety of systems, from ecological communities to human physiology. However, failure of these early warning signals in some systems calls for a better understanding of their limitations. In particular, little is known about the generality of early warning signals in different deteriorating environments. In this study, we characterized how multiple environmental drivers influence the dynamics of laboratory yeast populations, which was previously shown to display alternative stable states [Dai et al., Science, 2012]. We observed that both the coefficient of variation and autocorrelation increased before population collapse in two slowly deteriorating environments, one with a rising death rate and the other one with decreasing nutrient availability. We compared the performance of early warning signals across multiple environments as "indicators for loss of resilience." We find that the varying performance is determined by how a system responds to changes in a specific driver, which can be captured by a relation between stability (recovery rate) and resilience (size of the basin of attraction). Furthermore, we demonstrate that the positive correlation between stability and resilience, as the essential assumption of indicators based on critical slowing down, can break down in this system when multiple environmental drivers are changed simultaneously. Our results suggest that the stability-resilience relation needs to be better understood for the application of early warning signals in different scenarios.early warning signals | population collapse | environmental drivers | stability-resilience relation

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“…Indeed, less than 0.1% of species on Earth have adapted fast enough to avoid extinction (20), and similarly, only ∼0.1% of precancerous lesions ever advance to cancer (21). Evolutionary properties of extinction may be exploitable in evolving tumors (22).…”

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confidence: 99%

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

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

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151

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Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

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Turning ecology and evolution against cancer

Cited by 278 publications

References 134 publications

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Relation between stability and resilience determines the performance of early warning signals under different environmental drivers

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

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