Publications by authors named "Joel S Brown"

92 Publications

Cancer in Africa: The Untold Story.

Front Oncol 2021 15;11:650117. Epub 2021 Apr 15.

Laboratory of BioInformatics bioMathematics, and bioStatistics (BIMS), Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.

Background: Despite rising incidence and mortality rates in Africa, cancer has been given low priority in the research field and in healthcare services. Indeed, 57% of all new cancer cases around the world occur in low income countries exacerbated by lack of awareness, lack of preventive strategies, and increased life expectancies. Despite recent efforts devoted to cancer epidemiology, statistics on cancer rates in Africa are often dispersed across different registries. In this study our goal included identifying the most promising prevention and treatment approaches available in Africa. To do this, we collated and analyzed the incidence and fatality rates for the 10 most common and fatal cancers in 56 African countries grouped into 5 different regions (North, West, East, Central and South) over 16-years (2002-2018). We examined temporal and regional trends by investigating the most important risk factors associated to each cancer type. Data were analyzed by cancer type, African region, gender, measures of socioeconomic status and the availability of medical devices.

Results: We observed that Northern and Southern Africa were most similar in their cancer incidences and fatality rates compared to other African regions. The most prevalent cancers are breast, bladder and liver cancers in Northern Africa; prostate, lung and colorectal cancers in Southern Africa; and esophageal and cervical cancer in East Africa. In Southern Africa, fatality rates from prostate cancer and cervical cancer have increased. In addition, these three cancers are less fatal in Northern and Southern Africa compared to other regions, which correlates with the Human Development Index and the availability of medical devices. With the exception of thyroid cancer, all other cancers have higher incidences in males than females.

Conclusion: Our results show that the African continent suffers from a shortage of medical equipment, research resources and epidemiological expertise. While recognizing that risk factors are interconnected, we focused on risk factors more or less specific to each cancer type. This helps identify specific preventive and therapeutic options in Africa. We see a need for implementing more accurate preventive strategies to tackle this disease as many cases are likely preventable. Opportunities exist for vaccination programs for cervical and liver cancer, genetic testing and use of new targeted therapies for breast and prostate cancer, and positive changes in lifestyle for lung, colorectal and bladder cancers. Such recommendations should be tailored for the different African regions depending on their disease profiles and specific needs.
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http://dx.doi.org/10.3389/fonc.2021.650117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082106PMC
April 2021

Identifying key questions in the ecology and evolution of cancer.

Evol Appl 2021 Apr 8;14(4):877-892. Epub 2021 Feb 8.

Department of Data Science and Knowledge Engineering Maastricht University Maastricht The Netherlands.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.
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http://dx.doi.org/10.1111/eva.13190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061275PMC
April 2021

Cycling hypoxia selects for constitutive HIF stabilization.

Sci Rep 2021 Mar 11;11(1):5777. Epub 2021 Mar 11.

Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, SRB4, 12902 Magnolia Drive, Tampa, FL, 33612, USA.

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the "Warburg Effect". We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.
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http://dx.doi.org/10.1038/s41598-021-85184-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952589PMC
March 2021

Novel evolutionary dynamics of small populations in breast cancer adjuvant and neoadjuvant therapy.

NPJ Breast Cancer 2021 Mar 11;7(1):26. Epub 2021 Mar 11.

Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Disseminated cancer cells (DCCs) are detected in the circulation and bone marrow of up to 40% of breast cancer (BC) patients with clinically localized disease. The formation of metastases is governed by eco-evolutionary interactions of DCCs with the tissue during the transition from microscopic populations to macroscopic disease. Here, we view BC adjuvant and neoadjuvant treatments in the context of small population extinction dynamics observed in the Anthropocene era. Specifically, the unique eco-evolutionary dynamics of small asexually reproducing cancer populations render them highly vulnerable to: (1) environmental and demographic fluctuations, (2) Allee effects, (3) genetic drift and (4) population fragmentation. Furthermore, these typically interact, producing self-reinforcing, destructive dynamics-termed the Extinction Vortex-eradicating the population even when none of the perturbations is individually capable of causing extinction. We propose that developing BC adjuvant and neoadjuvant protocols may exploit these dynamics to prevent recovery and proliferation of small cancer populations during and after treatment-termed "Eco-evolutionary rescue" in natural extinctions. We hypothesize more strategic application of currently available agents based on the extinction vulnerabilities of small populations could improve clinical outcomes.
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http://dx.doi.org/10.1038/s41523-021-00230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952601PMC
March 2021

Adaptive Therapy for Metastatic Melanoma: Predictions from Patient Calibrated Mathematical Models.

Cancers (Basel) 2021 Feb 16;13(4). Epub 2021 Feb 16.

Integrated Mathematical Oncology, H. Lee Moffitt Cancer and Research Institute, Tampa, FL 33612, USA.

Adaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points in a patient-specific manner. Here we develop a combination of mathematical models that examine interactions between drug-sensitive and resistant cells to facilitate melanoma adaptive therapy dosing and switch time points. The first model assumes genetically fixed drug-sensitive and -resistant popul tions that compete for limited resources. The second model considers phenotypic switching between drug-sensitive and -resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy, such as the number of initial sensitive cells, competitive effect, switching rate from resistant to sensitive cells, and sensitive cell growth rate. This study highlights that there is a range of potential patient-specific benefits of adaptive therapy and identifies parameters that modulate this benefit.
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http://dx.doi.org/10.3390/cancers13040823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920057PMC
February 2021

Frequency-dependent interactions determine outcome of competition between two breast cancer cell lines.

Sci Rep 2021 Mar 1;11(1):4908. Epub 2021 Mar 1.

Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL, USA.

Tumors are highly dynamic ecosystems in which diverse cancer cell subpopulations compete for space and resources. These complex, often non-linear interactions govern continuous spatial and temporal changes in the size and phenotypic properties of these subpopulations. Because intra-tumoral blood flow is often chaotic, competition for resources may be a critical selection factor in progression and prognosis. Here, we quantify resource competition using 3D spheroid cultures with MDA-MB-231 and MCF-7 breast cancer cells. We hypothesized that MCF-7 cells, which primarily rely on efficient aerobic glucose metabolism, would dominate the population under normal pH and low glucose conditions; and MDA-MB-231 cells, which exhibit high levels of glycolytic metabolism, would dominate under low pH and high glucose conditions. In spheroids with single populations, MCF-7 cells exhibited equal or superior intrinsic growth rates (density-independent measure of success) and carrying capacities (density-dependent measure of success) when compared to MDA-MB-231 cells under all pH and nutrient conditions. Despite these advantages, when grown together, MCF-7 cells do not always outcompete MDA-MB-231 cells. MDA-MB-231 cells outcompete MCF-7 cells in low glucose conditions and coexistence is achieved in low pH conditions. Under all conditions, MDA-MB-231 has a stronger competitive effect (frequency-dependent interaction) on MCF-7 cells than vice-versa. This, and the inability of growth rate or carrying capacity when grown individually to predict the outcome of competition, suggests a reliance on frequency-dependent interactions and the need for competition assays. We frame these results in a game-theoretic (frequency-dependent) model of cancer cell interactions and conclude that competition assays can demonstrate critical density-independent, density-dependent and frequency-dependent interactions that likely contribute to in vivo outcomes.
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http://dx.doi.org/10.1038/s41598-021-84406-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921689PMC
March 2021

Fisheries management as a Stackelberg Evolutionary Game: Finding an evolutionarily enlightened strategy.

PLoS One 2021 20;16(1):e0245255. Epub 2021 Jan 20.

Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, United States of America.

Fish populations subject to heavy exploitation are expected to evolve over time smaller average body sizes. We introduce Stackelberg evolutionary game theory to show how fisheries management should be adjusted to mitigate the potential negative effects of such evolutionary changes. We present the game of a fisheries manager versus a fish population, where the former adjusts the harvesting rate and the net size to maximize profit, while the latter responds by evolving the size at maturation to maximize the fitness. We analyze three strategies: i) ecologically enlightened (leading to a Nash equilibrium in game-theoretic terms); ii) evolutionarily enlightened (leading to a Stackelberg equilibrium) and iii) domestication (leading to team optimum) and the corresponding outcomes for both the fisheries manager and the fish. Domestication results in the largest size for the fish and the highest profit for the manager. With the Nash approach the manager tends to adopt a high harvesting rate and a small net size that eventually leads to smaller fish. With the Stackelberg approach the manager selects a bigger net size and scales back the harvesting rate, which lead to a bigger fish size and a higher profit. Overall, our results encourage managers to take the fish evolutionary dynamics into account. Moreover, we advocate for the use of Stackelberg evolutionary game theory as a tool for providing insights into the eco-evolutionary consequences of exploiting evolving resources.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245255PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817040PMC
May 2021

Response to Mistry.

Nat Commun 2021 01 12;12(1):329. Epub 2021 Jan 12.

Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

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http://dx.doi.org/10.1038/s41467-020-20175-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804311PMC
January 2021

The Enemy Within: How Does a Bacterium Inhibit the Foraging Aptitude and Risk Management Behavior of Allenby's Gerbils?

Am Nat 2020 12 22;196(6):717-729. Epub 2020 Oct 22.

AbstractMicrobes inhabiting multicellular organisms have complex, often subtle effects on their hosts. are commonly infected with -like bacteria, which may cause mild nutrient (choline, arginine) deficiencies. However, are there more serious ecological consequences of infection, such as effects on foraging aptitudes and risk management? We tested two alternatives: the nutrient compensation hypothesis (does nutrient deficiency induce infected gerbils to make up for the shortfall by foraging more and taking greater risks?) and (2) the lethargy hypothesis (do sick gerbils forage less, and are they compromised in their ability to detect predators or risky microhabitats?). We compared the foraging and risk management behavior of infected and noninfected gerbils. We experimentally infected gerbils with the bacteria, which allowed us to compare between noninfected, acutely infected (peak infection loads), and chronically infected (low infection loads) individuals. Our findings supported the lethargy hypothesis over the nutrient compensation hypothesis. Infected individuals incurred dramatically elevated foraging costs, including less efficient foraging, diminished "quality" of time spent vigilant, and increased owl predation. Interestingly, gerbils that were chronically infected (lower bacteria load) experienced larger ecological costs than acutely infected individuals (i.e., peak infection loads). This suggests that the debilitating effects of infection occur gradually, with a progressive decline in the quality of time gerbils allocated to foraging and managing risk. These increased long-term costs of infection demonstrate how small direct physiological costs of infection can lead to large indirect ecological costs. The indirect ecological costs of this parasite appear to be much greater than the direct physiological costs.
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http://dx.doi.org/10.1086/711397DOI Listing
December 2020

Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy.

Cancer Res 2021 02 10;81(4):1135-1147. Epub 2020 Nov 10.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.

Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka-Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost-turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. SIGNIFICANCE: Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0806DOI Listing
February 2021

The Evolution and Ecology of Resistance in Cancer Therapy.

Cold Spring Harb Perspect Med 2020 11 2;10(11). Epub 2020 Nov 2.

Cancer Biology and Evolution Program.

Despite the continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of the human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires molecular machinery necessary to eliminate the cytotoxic effect of the treatment. However, the emergence of a resistant phenotype is not in itself clinically significant. That is, resistant cells affect patient outcomes only when they succeed in the second step of resistance by proliferating into a sufficiently large population to allow tumor progression and treatment failure. Importantly, proliferation of the resistant phenotype is by no means certain and, in fact, depends on complex Darwinian dynamics governed by the costs and benefits of the resistance mechanisms in the context of the local environment and competing populations. Attempts to target the molecular machinery of resistance have had little clinical success largely because of the diversity within the human genome-therapeutic interruption of one mechanism simply results in its replacement by an alternative. Here we explore evolutionarily informed strategies (adaptive, double-bind, and extinction therapies) for overcoming treatment resistance that seek to understand and exploit the critical evolutionary dynamics that govern proliferation of the resistant phenotypes. In general, this approach has demonstrated that, while emergence of resistance mechanisms in cancer cells to every current therapy is inevitable, proliferation of the resistant phenotypes is not and can be delayed and even prevented with sufficient understanding of the underlying eco-evolutionary dynamics.
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http://dx.doi.org/10.1101/cshperspect.a040972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605238PMC
November 2020

Unstable population dynamics in obligate co-operators.

Theor Popul Biol 2020 12 6;136:1-11. Epub 2020 Oct 6.

Department of Biological Sciences, University of Illinois at Chicago, 845 W. Taylor St. (M/C 066), Chicago, IL 60607, United States of America; Integrated Mathematical Oncology, Moffitt Cancer Center, SRB-4, 12902 USF Magnolia Drive Tampa, FL 33612, United States of America.

Cooperation significantly impacts a species' population dynamics as individuals choose others to associate with based upon fitness opportunities. Models of these dynamics typically assume that individuals can freely move between groups. Such an assumption works well for facultative co-operators (e.g. flocking birds, schooling fish, and swarming locusts) but less so for obligate co-operators (e.g. canids, cetaceans, and primates). With obligate co-operators, the fitness consequences from associations are stronger compared to facultative co-operators. Consequently, individuals within a group should be more discerning and selective over their associations, rejecting new members and even removing current members. Incorporating such aspects into population models may better reflect obligately cooperative species. In this paper, we create and analyze a model of the population dynamics of obligate co-operators. In our model, a behavioral game determines within-group population dynamics that then spill over into between-group dynamics. Our analysis shows that group number increases when population dynamics are stable, but additional groups lead to unstable population dynamics and an eventual collapse of group numbers. Using a more general analysis, we identify a fundamental mismatch between the stability of the behavioral dynamics and the stability of the population dynamics. When one is stable, the other is not. Our results suggest that group turnover may be inherent to the population dynamics of obligate co-operators. The instability arises from a non-chaotic deterministic process, and such dynamics should be predictable and testable.
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http://dx.doi.org/10.1016/j.tpb.2020.09.002DOI Listing
December 2020

Artificial selection for host resistance to tumour growth and subsequent cancer cell adaptations: an evolutionary arms race.

Br J Cancer 2021 01 7;124(2):455-465. Epub 2020 Oct 7.

Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Background: Cancer progression is governed by evolutionary dynamics in both the tumour population and its host. Since cancers die with the host, each new population of cancer cells must reinvent strategies to overcome the host's heritable defences. In contrast, host species evolve defence strategies over generations if tumour development limits procreation.

Methods: We investigate this "evolutionary arms race" through intentional breeding of immunodeficient SCID and immunocompetent Black/6 mice to evolve increased tumour suppression. Over 10 generations, we injected Lewis lung mouse carcinoma cells [LL/2-Luc-M38] and selectively bred the two individuals with the slowest tumour growth at day 11. Their male progeny were hosts in the subsequent round.

Results: The evolved SCID mice suppressed tumour growth through biomechanical restriction from increased mesenchymal proliferation, and the evolved Black/6 mice suppressed tumour growth by increasing immune-mediated killing of cancer cells. However, transcriptomic changes of multicellular tissue organisation and function genes allowed LL/2-Luc-M38 cells to adapt through increased matrix remodelling in SCID mice, and reduced angiogenesis, increased energy utilisation and accelerated proliferation in Black/6 mice.

Conclusion: Host species can rapidly evolve both immunologic and non-immunologic tumour defences. However, cancer cell plasticity allows effective phenotypic and population-based counter strategies.
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http://dx.doi.org/10.1038/s41416-020-01110-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852689PMC
January 2021

The context dependence of non-consumptive predator effects.

Ecol Lett 2021 Jan 29;24(1):113-129. Epub 2020 Sep 29.

School of Forestry and Environmental Studies, Yale University, 195 Prospect Street, New Haven, CT, 06511, USA.

Non-consumptive predator effects (NCEs) are now widely recognised for their capacity to shape ecosystem structure and function. Yet, forecasting the propagation of these predator-induced trait changes through particular communities remains a challenge. Accordingly, focusing on plasticity in prey anti-predator behaviours, we conceptualise the multi-stage process by which predators trigger direct and indirect NCEs, review and distil potential drivers of contingencies into three key categories (properties of the prey, predator and setting), and then provide a general framework for predicting both the nature and strength of direct NCEs. Our review underscores the myriad factors that can generate NCE contingencies while guiding how research might better anticipate and account for them. Moreover, our synthesis highlights the value of mapping both habitat domains and prey-specific patterns of evasion success ('evasion landscapes') as the basis for predicting how direct NCEs are likely to manifest in any particular community. Looking ahead, we highlight two key knowledge gaps that continue to impede a comprehensive understanding of non-consumptive predator-prey interactions and their ecosystem consequences; namely, insufficient empirical exploration of (1) context-dependent indirect NCEs and (2) the ways in which direct and indirect NCEs are shaped interactively by multiple drivers of context dependence.
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http://dx.doi.org/10.1111/ele.13614DOI Listing
January 2021

Integrating genetic and nongenetic drivers of somatic evolution during carcinogenesis: The biplane model.

Evol Appl 2020 Aug 13;13(7):1651-1659. Epub 2020 May 13.

Cancer Biology and Evolution Program Moffitt Cancer Center Tampa FL USA.

The multistep transition from a normal to a malignant cellular phenotype is often termed "somatic evolution" caused by accumulating random mutations. Here, we propose an alternative model in which the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host. However, these mutations are not carcinogenic because normal cells in multicellular organism cannot ordinarily evolve. That is, proliferation and death of normal cells are controlled by local tissue constraints typically governed by nongenomic information dynamics in the cell membrane. As a result, the cells of a multicellular organism have a fitness that is identical to the host, which is then the unit of natural selection. Somatic evolution of a cell can occur only when its fate becomes independent of host constraints. Now, survival, proliferation, and death of individual cells are dependent on Darwinian dynamics. This cellular transition from host-defined fitness to self-defined fitness may, consistent with the conventional view of carcinogenesis, result from mutations that render the cell insensitive to host controls. However, an identical state will result when surrounding tissue cannot exert control because of injury, inflammation, aging, or infection. Here, all surviving cells within the site of tissue damage default to self-defined fitness functions allowing them to evolve so that the mutations accumulated over the lifetime of the host now serve as the genetic heritage of an evolutionary unit of selection. Furthermore, tissue injury generates a new ecology cytokines and growth factors that might promote proliferation in cells with prior receptor mutations. This model integrates genetic and nongenetic dynamics into cancer development and is consistent with both clinical observations and prior experiments that divided carcinogenesis to initiation, promotion, and progression steps.
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http://dx.doi.org/10.1111/eva.12973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484850PMC
August 2020

Poly-aneuploid cancer cells promote evolvability, generating lethal cancer.

Evol Appl 2020 Aug 22;13(7):1626-1634. Epub 2020 Feb 22.

The Brady Urological Institute Johns Hopkins School of Medicine Baltimore MD USA.

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor-natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly-aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure-without the eradication of the resilient PACCs, cancer will recur in treated patients.
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http://dx.doi.org/10.1111/eva.12929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484876PMC
August 2020

Cancer Community Ecology.

Cancer Control 2020 Jan-Dec;27(1):1073274820951776

Department of Integrated Mathematical Oncology and Program in Cancer Biology and Evolution, 25301Moffitt Cancer Center, Tampa, FL, USA.

Here we advocate as a valuable focus of study in . We hypothesize that the heterogeneity and characteristics of cancer cells within tumors should vary systematically in space and time and that cancer cells form local ecological communities within tumors. These communities possess limited numbers of species determined by local conditions, with each species in a community possessing predictable traits that enable them to cope with their particular environment and coexist with each other. We start with a discussion of concepts and assumptions that ecologists use to study closely related species. We then discuss the competitive exclusion principle as a means for knowing when two species should not coexist, and as an opening towards understanding how they can. We present the five major categories of mechanisms of coexistence that operate in nature and suggest that the same mechanisms apply towards understanding the diversification and coexistence of cancer cell species. They are: Food-Safety Tradeoffs, Diet Choice, Habitat Selection, Variance Partitioning, and Competition-Colonization Tradeoffs. For each mechanism, we discuss how it works in nature, how it might work in cancers, and its implications for therapy.
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http://dx.doi.org/10.1177/1073274820951776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503020PMC
May 2021

What Is the Storage Effect, Why Should It Occur in Cancers, and How Can It Inform Cancer Therapy?

Cancer Control 2020 Jul-Aug;27(3):1073274820941968

Ecology Center & Department of Biology, Utah State University, Logan, UT, USA.

Intratumor heterogeneity is a feature of cancer that is associated with progression, treatment resistance, and recurrence. However, the mechanisms that allow diverse cancer cell lineages to coexist remain poorly understood. The storage effect is a coexistence mechanism that has been proposed to explain the diversity of a variety of ecological communities, including coral reef fish, plankton, and desert annual plants. Three ingredients are required for there to be a storage effect: (1) temporal variability in the environment, (2) buffered population growth, and (3) species-specific environmental responses. In this article, we argue that these conditions are observed in cancers and that it is likely that the storage effect contributes to intratumor diversity. Data that show the temporal variation within the tumor microenvironment are needed to quantify how cancer cells respond to fluctuations in the tumor microenvironment and what impact this has on interactions among cancer cell types. The presence of a storage effect within a patient's tumors could have a substantial impact on how we understand and treat cancer.
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http://dx.doi.org/10.1177/1073274820941968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658723PMC
March 2021

Integrating evolutionary dynamics into cancer therapy.

Nat Rev Clin Oncol 2020 11 22;17(11):675-686. Epub 2020 Jul 22.

Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL, USA.

Many effective drugs for metastatic and/or advanced-stage cancers have been developed over the past decade, although the evolution of resistance remains the major barrier to disease control or cure. In large, diverse populations such as the cells that compose metastatic cancers, the emergence of cells that are resistant or that can quickly develop resistance is virtually inevitable and most likely cannot be prevented. However, clinically significant resistance occurs only when the pre-existing resistant phenotypes are able to proliferate extensively, a process governed by eco-evolutionary dynamics. Attempts to disrupt the molecular mechanisms of resistance have generally been unsuccessful in clinical practice. In this Review, we focus on the Darwinian processes driving the eco-evolutionary dynamics of treatment-resistant cancer populations. We describe a variety of evolutionarily informed strategies designed to increase the probability of disease control or cure by anticipating and steering the evolutionary dynamics of acquired resistance.
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http://dx.doi.org/10.1038/s41571-020-0411-1DOI Listing
November 2020

High School Internship Program in Integrated Mathematical Oncology (HIP IMO): Five-Year Experience at Moffitt Cancer Center.

Bull Math Biol 2020 07 9;82(7):91. Epub 2020 Jul 9.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Modern cancer research, and the wealth of data across multiple spatial and temporal scales, has created the need for researchers that are well versed in the life sciences (cancer biology, developmental biology, immunology), medical sciences (oncology) and natural sciences (mathematics, physics, engineering, computer sciences). College undergraduate education traditionally occurs in disciplinary silos, which creates a steep learning curve at the graduate and postdoctoral levels that increasingly bridge multiple disciplines. Numerous colleges have begun to embrace interdisciplinary curricula, but students who double major in mathematics (or other quantitative sciences) and biology (or medicine) remain scarce. We identified the need to educate junior and senior high school students about integrating mathematical and biological skills, through the lens of mathematical oncology, to better prepare students for future careers at the interdisciplinary interface. The High school Internship Program in Integrated Mathematical Oncology (HIP IMO) at Moffitt Cancer Center has so far trained 59 students between 2015 and 2019. We report here on the program structure, training deliverables, curriculum and outcomes. We hope to promote interdisciplinary educational activities early in a student's career.
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http://dx.doi.org/10.1007/s11538-020-00768-1DOI Listing
July 2020

Intercontinental test of constraint-breaking adaptations: Testing behavioural plasticity in the face of a predator with novel hunting strategies.

J Anim Ecol 2020 08 23;89(8):1837-1850. Epub 2020 Apr 23.

Mathematical Oncology, Moffitt Cancer Research Center, Tampa, FL, USA.

Constraint-breaking adaptations are evolutionary tools that provide a mechanism for incumbent-replacement between species filling similar ecological roles. In common-garden experiments, we exposed populations of two desert rodents to two different viper species, testing their ability to adjust to novel predators that use different hunting strategies. We aimed to understand whether both predators and prey with constraint-breaking adaptations actually manifest comparative advantage over their counterparts. We used convergent species from desert dunes in the Mojave Desert in North America, Merriam's kangaroo rat Dipodomys merriami and the sidewinder rattlesnake Crotalus cerastes, and from the Negev Desert in the Middle East, the greater Egyptian gerbil Gerbillus pyramidum and the Saharan horned viper Cerastes cerastes. Both Mojave species hold constraint-breaking adaptations in relation to their counterparts from the Negev. The rattlesnakes have heat sensing organs (pits) and the kangaroo rats have fur-lined cheek pouches that allow for greater foraging efficiency and food preservation. Using patch-use theory, we evaluated the rodents' risk-assessment from each snake-separately, together and in combination with barn owls. Initially each rodent species foraged less in the presence of its familiar snake, but within a month both foraged less in the presence of the pit-viper (sidewinder). Our findings indicate a level of learning, and behavioural plasticity, in both rodents and ability to assess the risk from novel predators. The kangaroo rats were capable of harvesting far greater amounts of resources under the same conditions of elevated risk. However, the reason for their advantage may lie in bi-pedal agility and not only their ability collect food more efficiently.
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http://dx.doi.org/10.1111/1365-2656.13234DOI Listing
August 2020

Convergent Evolution, Evolving Evolvability, and the Origins of Lethal Cancer.

Mol Cancer Res 2020 06 31;18(6):801-810. Epub 2020 Mar 31.

Cancer Biology and Evolution Program and Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida.

Advances in curative treatment to remove the primary tumor have increased survival of localized cancers for most solid tumor types, yet cancers that have spread are typically incurable and account for >90% of cancer-related deaths. Metastatic disease remains incurable because, somehow, tumors evolve resistance to all known compounds, including therapies. In all of these incurable patients, lethal cancer evolves capacities for both metastasis and resistance. Therefore, cancers in different patients appear to follow the same eco-evolutionary path that independently manifests in affected patients. This convergent outcome, that always includes the ability to metastasize and exhibit resistance, demands an explanation beyond the slow and steady accrual of stochastic mutations. The common denominator may be that cancer starts as a speciation event when a unicellular protist breaks away from its multicellular host and initiates a cancer clade within the patient. As the cancer cells speciate and diversify further, some evolve the capacity to evolve: evolvability. Evolvability becomes a heritable trait that influences the available variation of other phenotypes that can then be acted upon by natural selection. Evolving evolvability may be an adaptation for cancer cells. By generating and maintaining considerable heritable variation, the cancer clade can, with high certainty, serendipitously produce cells resistant to therapy and cells capable of metastasizing. Understanding that cancer cells can swiftly evolve responses to novel and varied stressors create opportunities for adaptive therapy, double-bind therapies, and extinction therapies; all involving strategic decision making that steers and anticipates the convergent coevolutionary responses of the cancers.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272288PMC
June 2020

Towards Multidrug Adaptive Therapy.

Cancer Res 2020 04 16;80(7):1578-1589. Epub 2020 Jan 16.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

A new ecologically inspired paradigm in cancer treatment known as "adaptive therapy" capitalizes on competitive interactions between drug-sensitive and drug-resistant subclones. The goal of adaptive therapy is to maintain a controllable stable tumor burden by allowing a significant population of treatment-sensitive cells to survive. These, in turn, suppress proliferation of the less-fit resistant populations. However, there remain several open challenges in designing adaptive therapies, particularly in extending these therapeutic concepts to multiple treatments. We present a cancer treatment case study (metastatic castrate-resistant prostate cancer) as a point of departure to illustrate three novel concepts to aid the design of multidrug adaptive therapies. First, frequency-dependent "cycles" of tumor evolution can trap tumor evolution in a periodic, controllable loop. Second, the availability and selection of treatments may limit the evolutionary "absorbing region" reachable by the tumor. Third, the velocity of evolution significantly influences the optimal timing of drug sequences. These three conceptual advances provide a path forward for multidrug adaptive therapy. SIGNIFICANCE: Driving tumor evolution into periodic, repeatable treatment cycles provides a path forward for multidrug adaptive therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307613PMC
April 2020

Eradicating Metastatic Cancer and the Eco-Evolutionary Dynamics of Anthropocene Extinctions.

Cancer Res 2020 02 26;80(3):613-623. Epub 2019 Nov 26.

Cancer Biology and Evolution Program, Tampa, Florida.

Curative therapy for metastatic cancers is equivalent to causing extinction of a large, heterogeneous, and geographically dispersed population. Although eradication of dinosaurs is a dramatic example of extinction dynamics, similar application of massive eco-evolutionary force in cancer treatment is typically limited by host toxicity. Here, we investigate the evolutionary dynamics of Anthropocene species extinctions as an alternative model for curative cancer therapy. Human activities can produce extinctions of large, diverse, and geographically distributed populations. The extinction of a species typically follows a pattern in which initial demographic and ecological insults reduce the size and heterogeneity of the population. The surviving individuals, with decreased genetic diversity and often fragmented ecology, are then vulnerable to small stochastic perturbations that further reduce the population until extinction is inevitable. We hypothesize large, diverse, and disseminated cancer populations can be eradicated using similar evolutionary dynamics. Initial therapy is applied to reduce population size and diversity and followed by new treatments to exploit the eco-evolutionary vulnerability of small and/or declining populations. Mathematical models and computer simulations demonstrate initial reductive treatment followed immediately by demographic and ecological perturbations, similar to the empirically derived treatment of pediatric acute lymphocytic leukemia, can consistently achieve curative outcomes in nonpediatric cancers. SIGNIFICANCE: Anthropocene extinctions suggest a strategy for eradicating metastatic cancers in which initial therapy, by reducing the size and diversity of the population, renders it vulnerable to extinction by rapidly applied additional perturbations.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771333PMC
February 2020

First Strike-Second Strike Strategies in Metastatic Cancer: Lessons from the Evolutionary Dynamics of Extinction.

Cancer Res 2019 07 20;79(13):3174-3177. Epub 2019 Jun 20.

Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, Florida.

While clinical cancer research has produced many highly effective drugs, the diversity and evolutionary capacity of most cancer populations remain insurmountable barriers to cure. Here, we propose that curative outcomes may, nevertheless, be achieved by sequencing therapies that are individually effective but noncurative. Basic principles for such an approach are derived from the eco-evolutionary dynamics of background extinctions in which a "first strike" reduces the size and heterogeneity of the population. When followed immediately by demographic and ecological "second strikes," the population can be reduced below some minimum threshold, leading inevitably to extinction. This strategy bears strong similarity to the empirically-derived curative therapy in childhood acute lymphocytic leukemia.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606376PMC
July 2019

Patch use in the arctic ground squirrel: effects of micro-topography and shrub encroachment in the Arctic Circle.

Oecologia 2019 May 23;190(1):243-254. Epub 2019 Apr 23.

Department of Biological Sciences, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL, 60607, USA.

We investigated the roles of vegetation structure, micro-topographic relief, and predator activity patterns (time of day) on the perception of predatory risk of arctic ground squirrels (Urocitellus parryii), an abundant pan-Arctic omnivore, in Arctic Circle tundra on the North Slope of Alaska, where tundra vegetation structure has been predicted to change in response to climate. We quantified foraging intensity by measuring the giving-up densities (GUDs) of the arctic ground squirrels in experimental foraging patches along a heath-graminoid-shrub moist tundra gradient. We hypothesized that foraging intensity of arctic ground squirrels would be greatest and GUDs lowest, where low-stature vegetation or raised micro-topography improves sightlines for predator detection. Furthermore, GUDs should vary with time of day and reflect 24-h cycles of varying predation risk. Foraging intensity varied temporally, being highest in the afternoon and lowest overnight. During the morning, foraging intensity was inversely correlated with the normalized difference vegetation index (NDVI), a proxy for vegetation productivity and cover. Foraging was additionally measured within landscapes of fear, confirming that vegetative and topographic obstructions of sightlines reduces foraging intensity and increases GUDs. We conclude that arctic ground squirrels may affect Arctic Circle vegetation of tundra ecosystems, but these effects will vary spatially and temporally.
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http://dx.doi.org/10.1007/s00442-019-04400-5DOI Listing
May 2019

Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy.

Clin Cancer Res 2019 07 16;25(14):4413-4421. Epub 2019 Apr 16.

Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, Florida.

Purpose: Integration of evolutionary dynamics into systemic therapy for metastatic cancers can prolong tumor control compared with standard maximum tolerated dose (MTD) strategies. Prior investigations have focused on monotherapy, but many clinical cancer treatments combine two or more drugs. Optimizing the evolutionary dynamics in multidrug therapy is challenging because of the complex cellular interactions and the large parameter space of potential variations in drugs, doses, and treatment schedules. However, multidrug therapy also represents an opportunity to further improve outcomes using evolution-based strategies.

Experimental Design: We examine evolution-based strategies for two-drug therapy and identify an approach that divides the treatment drugs into primary and secondary roles. The primary drug has the greatest efficacy and/or lowest toxicity. The secondary drug is applied solely to reduce the resistant population to the primary drug.

Results: Simulations from the mathematical model demonstrate that the primary-secondary approach increases time to progression (TTP) compared with conventional strategies in which drugs are administered without regard to evolutionary dynamics. We apply our model to an ongoing adaptive therapy clinical trial of evolution-based administration of abiraterone to treat metastatic castrate-resistant prostate cancer. Model simulations, parameterized with data from individual patients who progressed, demonstrate that strategic application of docetaxel during abiraterone therapy would have significantly increased their TTP.

Conclusions: Mathematical models can integrate evolutionary dynamics into multidrug cancer clinical trials. This has the potential to improve outcomes and to develop clinical trials in which these mathematical models are also used to estimate the mechanism(s) of treatment failure and explore alternative strategies to improve outcomes in future trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665681PMC
July 2019

Comparing Plasticity of Response to Perceived Risk in the Textbook Example of Convergent Evolution of Desert Rodents and Their Predators; a Manipulative Study Employing the Landscape of Fear.

Front Behav Neurosci 2019 22;13:58. Epub 2019 Mar 22.

Department of Biological Science, University of Illinois, Chicago, Chicago, IL, United States.

Foragers process information they gain from their surroundings to assess the risk from predators and balance it with the resources in their environment. Measuring these perceived risks from the perspective of the forager can produce a heatmap or their "fear" in the environments, a so-called "landscape of fear" (LOF). In an intercontinental comparison of rodents from the Mojave and Negev Deserts, we set to compare families that are used regularly as examples of convergent evolution, heteromyid and gerbilline respectively. Using a LOF spatial-analysis on data collected from common garden experiments in a semi-natural arena we asked: (1) do all four species understand the risk similarly in the exact same physical environment; (2) does relative relation between species affect the way species draw their LOFs, or does the evolutionary niche of a species have a greater impact on its LOF?; and (3) does predator facilitation between vipers and barn owls cause similar changes to the shape of the measured LOFs. For stronger comparative power we mapped the LOF of the rodents under two levels of risk: low risk (snakes only) and high risk (snakes and barn owls). We found concordance in the way all four species assessed risk in the arena. However, the patterns observed in the LOFs of each rodent family were different, and the way the topographic shape of the LOF changed when owls were introduced varied by species. Specifically, gerbils were more sensitive to owl-related risk than snakes and at the opposite correct for heteromyids. Our findings suggest that the community and environment in which a species evolved has a strong impact on the strategies said animals employ. We also conclude, that given the homogenous landscape we provide in our arena and the non- homogenous patterns of LOF maps, risk assessment can be independent of the physical conditions under which the animals find themselves.
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http://dx.doi.org/10.3389/fnbeh.2019.00058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440367PMC
March 2019

The impact of proliferation-migration tradeoffs on phenotypic evolution in cancer.

Sci Rep 2019 02 20;9(1):2425. Epub 2019 Feb 20.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Tumors are not static masses of cells but dynamic ecosystems where cancer cells experience constant turnover and evolve fitness-enhancing phenotypes. Selection for different phenotypes may vary with (1) the tumor niche (edge or core), (2) cell turnover rates, (3) the nature of the tradeoff between traits, and (4) whether deaths occur in response to demographic or environmental stochasticity. Using a spatially-explicit agent-based model, we observe how two traits (proliferation rate and migration speed) evolve under different tradeoff conditions with different turnover rates. Migration rate is favored over proliferation at the tumor's edge and vice-versa for the interior. Increasing cell turnover rates slightly slows tumor growth but accelerates the rate of evolution for both proliferation and migration. The absence of a tradeoff favors ever higher values for proliferation and migration, while a convex tradeoff tends to favor proliferation, often promoting the coexistence of a generalist and specialist phenotype. A concave tradeoff favors migration at low death rates, but switches to proliferation at higher death rates. Mortality via demographic stochasticity favors proliferation, and environmental stochasticity favors migration. While all of these diverse factors contribute to the ecology, heterogeneity, and evolution of a tumor, their effects may be predictable and empirically accessible.
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http://dx.doi.org/10.1038/s41598-019-39636-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382810PMC
February 2019
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