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1. Optimal dosing of anti-cancer treatment under drug-induced plasticity

   Gunnarsson, E; Magnússon, Benedikt Vilji; Foo, Jasmine (July 2025, Arxiv)

   While cancer has traditionally been considered a genetic disease, mounting evidence indicates an important role for non-genetic (epigenetic) mechanisms. Common anti-cancer drugs have recently been observed to induce the adoption of non-genetic drug-tolerant cell states, thereby accelerating the evolution of drug resistance. This confounds conventional high-dose treatment strategies aimed at maximal tumor reduction, since high doses can simultaneously promote non-genetic resistance. In this work, we study optimal dosing of anti-cancer treatment under drug-induced cell plasticity. We show that the optimal dosing strategy steers the tumor to a fixed equilibrium composition between sensitive and tolerant cells, while precisely balancing the trade-off between cell kill and tolerance induction. The optimal equilibrium strategy ranges from applying a low dose continuously to applying the maximum dose intermittently, depending on the dynamics of tolerance induction. We finally discuss how our approach can be integrated with in vitro data to derive patient-specific treatment insights. 

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2. Adaptive Phenotypic Plasticity Stabilizes Evolution in Fluctuating Environments

   https://doi.org/10.3389/fevo.2021.715381  

   Lalejini, Alexander; Ferguson, Austin J.; Grant, Nkrumah A.; Ofria, Charles (August 2021, Frontiers in Ecology and Evolution)

   Fluctuating environmental conditions are ubiquitous in natural systems, and populations have evolved various strategies to cope with such fluctuations. The particular mechanisms that evolve profoundly influence subsequent evolutionary dynamics. One such mechanism is phenotypic plasticity, which is the ability of a single genotype to produce alternate phenotypes in an environmentally dependent context. Here, we use digital organisms (self-replicating computer programs) to investigate how adaptive phenotypic plasticity alters evolutionary dynamics and influences evolutionary outcomes in cyclically changing environments. Specifically, we examined the evolutionary histories of both plastic populations and non-plastic populations to ask: (1) Does adaptive plasticity promote or constrain evolutionary change? (2) Are plastic populations better able to evolve and then maintain novel traits? And (3), how does adaptive plasticity affect the potential for maladaptive alleles to accumulate in evolving genomes? We find that populations with adaptive phenotypic plasticity undergo less evolutionary change than non-plastic populations, which must rely on genetic variation from de novo mutations to continuously readapt to environmental fluctuations. Indeed, the non-plastic populations undergo more frequent selective sweeps and accumulate many more genetic changes. We find that the repeated selective sweeps in non-plastic populations drive the loss of beneficial traits and accumulation of maladaptive alleles, whereas phenotypic plasticity can stabilize populations against environmental fluctuations. This stabilization allows plastic populations to more easily retain novel adaptive traits than their non-plastic counterparts. In general, the evolution of adaptive phenotypic plasticity shifted evolutionary dynamics to be more similar to that of populations evolving in a static environment than to non-plastic populations evolving in an identical fluctuating environment. All natural environments subject populations to some form of change; our findings suggest that the stabilizing effect of phenotypic plasticity plays an important role in subsequent adaptive evolution. 

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3. Evolution of transmissible cancers: an adaptive, plastic strategy of selfish genetic elements?

   https://doi.org/10.1016/j.isci.2024.110740  

   Reeve, Hudson Kern; Pfennig, David W (August 2024, iScience)

   Agrowing number of studies have applied evolutionary and ecological principles to understanding cancer.However, few such studies have examined whether phenotypic plasticity––the ability of a single individual or genome to respond differently to different environmental circumstances––can impact the origin and spread of cancer. Here, we propose the adaptive horizontal transmission hypothesis to explain how flexible decision-making by selfish genetic elements can cause them to spread from the genome of their original host into the genomes of other hosts through the evolution of transmissible cancers. Specifically, we hypothesize that such cancers appear when the likelihood of successful vertical transmission is sufficiently low relative to the likelihood of successful horizontal transmission. We develop an evolutionary optimization model of this hypothesis, highlight empirical findings that support it, and offer suggestions for future research. Generally, phenotypically plastic selfish genetic elements might play an important role in the evolution of transmissible cancers. 

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4. How stabilizing selection and nongenetic inheritance combine to shape the evolution of phenotypic plasticity

   https://doi.org/DOI: 10.1111/jeb.13475  

   Levis, N. A. Pfennig (April 2019, Journal of Evolutionary Biology Research)

   Relatively little is known about whether and how nongenetic inheritance interacts with selection to impact the evolution of phenotypic plasticity. Here, we empirically evaluated how stabilizing selection and a common form of nongenetic inheritance—maternal environmental effects—jointly influence the evolution of phenotypic plasticity in natural populations of spadefoot toads. We compared populations that previous fieldwork has shown to have evolved conspicuous plasticity in resource‐use phenotypes (“resource polyphenism”) with those that, owing to stabilizing selection favouring a narrower range of such phenotypes, appear to have lost this plasticity. We show that: (a) this apparent loss of plasticity in nature reflects a condition‐dependent maternal effect and not a genetic loss of plasticity, that is “genetic assimilation,” and (b) this plasticity is not costly. By shielding noncostly plasticity from selection, nongenetic inheritance generally, and maternal effects specifically, can preclude genetic assimilation from occurring and consequently impede adaptive (genetic) evolution. 

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5. Soil microbes influence the ecology and evolution of plant plasticity

   https://doi.org/10.1111/nph.20383  

   Bolin, Lana G (March 2025, New Phytologist)

   Summary Stress often induces plant trait plasticity, and microbial communities also alter plant traits. Therefore, it is unclear how much plasticity results from direct plant responses to stress vs indirect responses due to stress‐induced changes in soil microbial communities.To test how microbes and microbial community responses to stress affect the ecology and potentially the evolution of plant plasticity, I grew plants in four stress environments (salt, herbicide, herbivory, and no stress) with microbes that had responded to these same environments or with sterile inoculant.Plants delayed flowering under stress only when inoculated with live microbial communities, and this plasticity was maladaptive. However, microbial communities responded to stress in ways that accelerated flowering across all environments. Microbes also affected the expression of genetic variation for plant flowering time and specific leaf area, as well as genetic variation for plasticity of both traits, and disrupted a positive genetic correlation for plasticity in response to herbicide and herbivory stress, suggesting that microbes may affect the pace of plant evolution.Together, these results highlight an important role for soil microbes in plant plastic responses to stress and suggest that microbes may alter the evolution of plant plasticity. 

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