Athena Aktipis

Classifying the evolutionary and ecological features of neoplasms

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patients tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer

IntroductionAbundance of immune cells has been shown to have prognostic and predictive significance in many tumor types. Beyond abundance, the spatial organization of immune cells in relation to cancer cells may also have significant functional and clinical implications. However there is a lack of systematic methods to quantify spatial associations between immune and cancer cells.MethodsWe applied ecological measures of species interactions to digital pathology images for investigating the spatial associations of immune and cancer cells in breast cancer. We used the Morisita-Horn similarity index, an ecological measure of community structure and predator–prey interactions, to quantify the extent to which cancer cells and immune cells colocalize in whole-tumor histology sections. We related this index to disease-specific survival of 486 women with breast cancer and validated our findings in a set of 516 patients from different hospitals.ResultsColocalization of immune cells with cancer cells was significantly associated with a disease-specific survival benefit for all breast cancers combined. In HER2-positive subtypes, the prognostic value of immune-cancer cell colocalization was highly significant and exceeded those of known clinical variables. Furthermore, colocalization was a significant predictive factor for long-term outcome following chemotherapy and radiotherapy in HER2 and Luminal A subtypes, independent of and stronger than all known clinical variables.ConclusionsOur study demonstrates how ecological methods applied to the tumor microenvironment using routine histology can provide reproducible, quantitative biomarkers for identifying high-risk breast cancer patients. We found that the clinical value of immune-cancer interaction patterns is highly subtype-specific but substantial and independent to known clinicopathologic variables that mostly focused on cancer itself. Our approach can be developed into computer-assisted prediction based on histology samples that are already routinely collected.

Cooperation in an Uncertain World: For the Maasai of East Africa, Need-Based Transfers Outperform Account-Keeping in Volatile Environments.

Using an agent-based model to study risk-pooling in herder dyads using rules derived from Maasai osotua (“umbilical cord”) relationships, Aktipis et al. (2011) found that osotua transfers led to more risk-pooling and better herd survival than both no transfers and transfers that occurred at frequencies tied to those seen in the osotua simulations. Here we expand this approach by comparing osotua-style transfers to another type of livestock transfer among Maasai known as esile (“debt”). In osotua, one asks if in need, and one gives in response to such requests if doing so will not threaten one’s own survival. In esile relationships, accounts are kept and debts must be repaid. We refer to these as “need-based” and “account-keeping” systems, respectively. Need-based transfers lead to more risk pooling and higher survival than account keeping. Need-based transfers also lead to greater wealth equality and are game theoretically dominant to account-keeping rules.

Resource conflict and cooperation between human host and gut microbiota: implications for nutrition and health

Diet has been known to play an important role in human health since at least the time period of the ancient Greek physician Hippocrates. In the last decade, research has revealed that microorganisms inhabiting the digestive tract, known as the gut microbiota, are critical factors in human health. This paper draws on concepts of cooperation and conflict from ecology and evolutionary biology to make predictions about host–microbiota interactions involving nutrients. To optimally extract energy from some resources (e.g., fiber), hosts require cooperation from microbes. Other nutrients can be utilized by both hosts and microbes (e.g., simple sugars, iron) in their ingested form, which may lead to greater conflict over these resources. This framework predicts that some negative health effects of foods are driven by the direct effects of these foods on human physiology and by indirect effects resulting from microbiome–host competition and conflict (e.g., increased invasiveness and inflammation). Similarly, beneficial effects of some foods on host health may be enhanced by resource sharing and other cooperative behaviors between host and microbes that may downregulate inflammation and virulence. Given that some foods cultivate cooperation between hosts and microbes while others agitate conflict, host–microbe interactions may be novel targets for interventions aimed at improving nutrition and human health.

Principles of cooperation across systems: from human sharing to multicellularity and cancer.

From cells to societies, several general principles arise again and again that facilitate cooperation and suppress conflict. In this study, I describe three general principles of cooperation and how they operate across systems including human sharing, cooperation in animal and insect societies and the massively large‐scale cooperation that occurs in our multicellular bodies. The first principle is that of Walk Away: that cooperation is enhanced when individuals can leave uncooperative partners. The second principle is that resource sharing is often based on the need of the recipient (i.e., need‐based transfers) rather than on strict account‐keeping. And the last principle is that effective scaling up of cooperation requires increasingly sophisticated and costly cheater suppression mechanisms. By comparing how these principles operate across systems, we can better understand the constraints on cooperation. This can facilitate the discovery of novel ways to enhance cooperation and suppress cheating in its many forms, from social exploitation to cancer.

Cooperation and cheating as innovation: insights from cellular societies

The capacity to innovate is often considered a defining feature of human societies, but it is not a capacity that is unique to human societies: innovation occurs in cellular societies as well. Cellular societies such as multicellular bodies and microbial communities, including the human microbiome, are capable of innovation in response to novel opportunities and threats. Multicellularity represents a suite of innovations for cellular cooperation, but multicellularity also opened up novel opportunities for cells to cheat, exploiting the infrastructure and resources of the body. Multicellular bodies evolve less quickly than the cells within them, leaving them vulnerable to cellular innovations that can lead to cancer and infections. In order to counter these threats, multicellular bodies deploy additional innovations including the adaptive immune system and the development of partnerships with preferred microbial partners. What can we learn from examining these innovations in cooperation and cheating in cellular societies? First, innovation in social systems involves a constant tension between novel mechanisms that enable greater size and complexity of cooperative entities and novel ways of cheating. Second, cultivating cooperation with partners who can rapidly and effectively innovate (such as microbes) is important for large entities including multicellular bodies. And third, multicellularity enabled cells to manage risk socially, allowing organisms to survive in challenging environments where life would otherwise be impossible. Throughout, we ask how insights from cellular societies might be translated into new innovations in human health and medicine, promoting and protecting the cellular cooperation that makes us viable multicellular organisms. This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.

The Darwinian Dynamics of Motility and Metastasis

Cancer is a deadly disease, but it is rarely the primary tumor that kills patients. Most cancer deaths are due to metastasis, a complex and still poorly understood process. Metastatic cells may be particularly deadly not just because they can colonize new sites, but because they exhibit a much more plastic and adaptable phenotype compared to primary tumor cells. In this chapter we provide an overview of the evolution of metastasis. First, we review what is known about the mechanisms underlying cell motility/metastasis. Then we describe how evolution operates on cell motility, how evolution operates within tumors, how selection among micrometastases may be important and the role of co-evolution between tumor and stromal cells during metastasis. In addition to reviewing the literature, we describe a number of important insights from evolution that can help guide future work on the nature and dynamics of metastases. These include the application of ecological dispersal theory to the evolution of cell motility, the fact that somatic selection can favor plasticity in neoplastic cells, the possibility that selection among micrometastases may lead to the evolution of collective phenotypes that can extract resources from the host body, and the observation that the parameters of evolution may differ dramatically between primary tumors and metastases. By targeting the processes of evolution of cell motility, cell plasticity and the ability of cells to alter their environments, it may be possible for clinicians to substantially extend life and improve the quality of life for cancer patients. Evolutionary and ecological tools and approaches can help provide a basic framework for integrating what is already known about the evolution of metastasis and guiding future work on this topic.

Understanding cooperation through fitness interdependence

Some acts of human cooperation are not easily explained by traditional models of kinship or reciprocity. Fitness interdependence may provide a unifying conceptual framework, in which cooperation arises from the mutual dependence for survival or reproduction, as occurs among mates, risk-pooling partnerships and brothers-in-arms.

Kombucha as a model system for multispecies microbial cooperation: theoretical promise, methodological challenges and new solutions 'in solution'

Kombucha is a sweetened tea fermented by bacteria and yeast into a carbonated, acidic drink, producing a surface biofilm pellicle (colloquially called a SCOBY) during the process. Typically, liquid and a biofilm pellicle from a previously fermented culture is used as a starter for new cultures; however, there is no standard protocol for growing kombucha in the laboratory. In order to establish a standard protocol with low variability between replicates, we tested whether we could begin a kombucha culture with only well-mixed liquid stock. We found that viable kombucha cultures can be grown from low percentages of initial inoculum stock liquid, that new pellicles can form from liquid alone (with no ‘starter’ pellicle), and that the variation in the pellicle characteristics is lower when only a liquid starter is used (p = 0.0004). We also found that blending the pellicle before including it significantly reduces the variation among replicates, though the final pellicle was abnormal. We conclude that growing kombucha from only liquid stock is viable and provides a greater degree of experimental control and reproducibility compared to alternatives. Standardizing methodologies for studying kombucha in the lab can facilitate the use of this system for exploring questions about the evolutionary, ecological and cooperative/competitive dynamics within this multi-species system including resource transfers, functional dependence, genetic divergence, collective defense, and ecological succession. A better understanding of kombucha and other fermented foods may eventually allow us to leverage their pathogen inhibitory properties to develop novel antibiotics and bacteriocins.

Correlated disasters and need-based transfers: The limits of risk pooling systems in simulated ecologies

Throughout their evolutionary history, humans have faced risks including drought, disease, natural disasters and other unexpected negative events. To deal with these risks, humans use a variety of risk management strategies, some of which involve relying on others in times of need in order to pool risk. However, the effectiveness of risk pooling strategies can be limited when there is high synchronicity of need. Here we investigate the limits of two resource transfer systems for pooling risk (need-based transfers, NBT, and debt-based transfers, DBT) in simulated ecologies with different degrees of correlated disasters using an agent-based model of the need-based transfer system of the Maasai. Overall, we find that survival is higher when shocks are less correlated among partners, when groups are larger, and when network structure is characterized by preferential attachment networks, which have a more modular structure than regular or small world networks. We also find that NBT strategies consistently outperform DBT strategies across a wide variety of parameter values and that the advantage of NBT over DBT is greatest when shocks are less correlated and group size is small. Our results also suggest that systems of sharing that are based on recipient need are less vulnerable than systems that are based on debt and credit, especially in small world and regular networks.