Evolution at the edge of expanding populations

Predicting evolution of expanding populations is critical to control biological threats such as invasive species and cancer metastasis. Expansion is primarily driven by reproduction and dispersal, but nature abounds with examples of evolution where organisms pay a reproductive cost to disperse faster. When does selection favor this 'survival of the fastest?' We searched for a simple rule, motivated by evolution experiments where swarming bacteria evolved into an hyperswarmer mutant which disperses $\sim 100\%$ faster but pays a growth cost of $\sim 10 \%$ to make many copies of its flagellum. We analyzed a two-species model based on the Fisher equation to explain this observation: the population expansion rate ($v$) results from an interplay of growth ($r$) and dispersal ($D$) and is independent of the carrying capacity: $v=2\sqrt{rD}$. A mutant can take over the edge only if its expansion rate ($v_2$) exceeds the expansion rate of the established species ($v_1$); this simple condition ($v_2 > v_1$) determines the maximum cost in slower growth that a faster mutant can pay and still be able to take over. Numerical simulations and time-course experiments where we tracked evolution by imaging bacteria suggest that our findings are general: less favorable conditions delay but do not entirely prevent the success of the fastest. Thus, the expansion rate defines a traveling wave fitness, which could be combined with trade-offs to predict evolution of expanding populations

A simple rule for the evolution of fast dispersal at the edge of expanding populations

Evolution by natural selection is commonly perceived as a process that favors those that replicate faster to leave more offspring; nature, however, seem to abound with examples where organisms forgo some replicative potential to disperse faster. When does selection favor invasion of the fastest? Motivated by evolution experiments with swarming bacteria we searched for a simple rule. In experiments, a fast hyperswarmer mutant that pays a reproductive cost to make many copies of its flagellum invades a population of mono-flagellated bacteria by reaching the expanding population edge; a two-species mathematical model explains that invasion of the edge occurs only if the invasive species' expansion rate, v₂, which results from the combination of the species growth rate and its dispersal speed (but not its carrying capacity), exceeds the established species', v₁. The simple rule that we derive, v₂ > v₁, appears to be general: less favorable initial conditions, such as smaller initial sizes and longer distances to the population edge, delay but do not entirely prevent invasion. Despite intricacies of the swarming system, experimental tests agree well with model predictions suggesting that the general theory should apply to other expanding populations with trade-offs between growth and dispersal, including non-native invasive species and cancer metastases.First author draf

Directional migration of the neural crest: an interplay between contact inhibition of locomotion and co-attraction

Collective cell migration is recognised as a common feature of cell movement in vivo. Despite its importance for both morphogenesis and malignant progression, little is known about how directional and coordinated cell movements are regulated collectively. An interesting example of collective migration in vivo is the migration of Neural Crest (NC) cells. NC cells are highly migratory and multipotent embryonic cells, which migrate with remarkable directionality and coordination. In this thesis it is proposed that a mayor force in allowing NC collective directionality is given by local cell-cell interactions. Two main interactions, a repulsive and an attractive one, are identified here and their role in NC migration is analysed. First, it is shown that Contact Inhibition of Locomotion (CIL) is essential for NC migration. These cells collapse their protrusions upon contact with others and polarise towards cell-free regions leading to cell dispersion. Also, it is shown that the non-canonical Wnt signalling is crucial in this process as its members localise at the site of contact. This leads to activation of RhoA and inhibition of cell protrusions in this region. These results provide one of the rst examples of CIL in vivo and establish a novel role for non-canonical Wnt signalling. Second, a longer-range attractive interaction is also described here in a novel mechanism termed coattraction. It is shown in silico, in vitro and in vivo that when CIL is combined with coattraction, directional collective movements emerge instead of the simple dispersion allowed by CIL. Surprisingly, it was found that the anaphylatoxin/chemoattractant C3a and its receptor C3aR mediate NC coattraction. Finally, it is proposed that CIL and coattraction act together to allow cell collectives, such as the NC, to self-organise allowing a more effcient response to external signals such as chemoattractants and restrictive cues

Preferencias dependientes y determinación del mercado relevante

La Economía del Comportamiento ha cuestionado algunos de los principios de la Economía Neoclásica Liberal, postulando que existen ciertos límites a la racionalidad de las personas no considerados por la economía tradicional, los cuales serían relevantes al prever las conductas de las personas. Los avances de la Economía del Comportamiento se han extendido al análisis económico del derecho, haciendo ver diversas situaciones en donde esta nueva visión otorga predicciones y resultados diversos a los que ha otorgado el análisis económico del derecho tradicional. Dentro de esta línea de investigación, este trabajo pretende aportar elementos nuevos en la determinación del mercado relevante en el derecho de la libre competencia. Sostenemos que en razón de la dependencia del contexto a la cual está sujeta la elección de las personas, las relaciones de sustitución entre diferentes bienes no es siempre la que espera la Economía Neoclásica Liberal

Metabolic origins of spatial organization in the tumor microenvironment.

The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity

Mesoderm is required for coordinated cell movements within zebrafish neural plate in vivo.

BACKGROUND: Morphogenesis of the zebrafish neural tube requires the coordinated movement of many cells in both time and space. A good example of this is the movement of the cells in the zebrafish neural plate as they converge towards the dorsal midline before internalizing to form a neural keel. How these cells are regulated to ensure that they move together as a coherent tissue is unknown. Previous work in other systems has suggested that the underlying mesoderm may play a role in this process but this has not been shown directly in vivo. RESULTS: Here we analyze the roles of subjacent mesoderm in the coordination of neural cell movements during convergence of the zebrafish neural plate and neural keel formation. Live imaging demonstrates that the normal highly coordinated movements of neural plate cells are lost in the absence of underlying mesoderm and the movements of internalization and neural tube formation are severely disrupted. Despite this, neuroepithelial polarity develops in the abnormal neural primordium but the resulting tissue architecture is very disorganized. CONCLUSIONS: We show that the movements of cells in the zebrafish neural plate are highly coordinated during the convergence and internalization movements of neurulation. Our results demonstrate that the underlying mesoderm is required for these coordinated cell movements in the zebrafish neural plate in vivo

Delamination of neural crest cells requires transient and reversible Wnt inhibition mediated by DACT1/2

Delamination of neural crest (NC) cells is a bona fide physiological model of epithelial-to-mesenchymal transition (EMT), a process that is influenced by Wnt/β-catenin signalling. Using two in vivo models, we show that Wnt/β-catenin signalling is transiently inhibited at the time of NC delamination. In attempting to define the mechanism underlying this inhibition, we found that the scaffold proteins Dact1 and Dact2, which are expressed in pre-migratory NC cells, are required for NC delamination in Xenopus and chick embryos, whereas they do not affect the motile properties of migratory NC cells. Dact1/2 inhibit Wnt/β-catenin signalling upstream of the transcriptional activity of T cell factor (TCF), which is required for EMT to proceed. Dact1/2 regulate the subcellular distribution of β-catenin, preventing β-catenin from acting as a transcriptional co-activator to TCF, yet without affecting its stability. Together, these data identify a novel yet important regulatory element that inhibits β-catenin signalling, which then affects NC delamination

Multiscale mechanisms of cell migration during development: theory and experiment

Long-distance cell migration is an important feature of embryonic development, adult morphogenesis and cancer, yet the mechanisms that drive subpopulations of cells to distinct targets are poorly understood. Here, we use the embryonic neural crest (NC) in tandem with theoretical studies to evaluate model mechanisms of long-distance cell migration. We find that a simple chemotaxis model is insufficient to explain our experimental data. Instead, model simulations predict that NC cell migration requires leading cells to respond to long-range guidance signals and trailing cells to short-range cues in order to maintain a directed, multicellular stream. Experiments confirm differences in leading versus trailing NC cell subpopulations, manifested in unique cell orientation and gene expression patterns that respond to non-linear tissue growth of the migratory domain. Ablation experiments that delete the trailing NC cell subpopulation reveal that leading NC cells distribute all along the migratory pathway and develop a leading/trailing cellular orientation and gene expression profile that is predicted by model simulations. Transplantation experiments and model predictions that move trailing NC cells to the migratory front, or vice versa, reveal that cells adopt a gene expression profile and cell behaviors corresponding to the new position within the migratory stream. These results offer a mechanistic model in which leading cells create and respond to a cell-induced chemotactic gradient and transmit guidance information to trailing cells that use short-range signals to move in a directional manner

Directional collective cell migration emerges as a property of cell interactions.

Collective cell migration is a fundamental process, occurring during embryogenesis and cancer metastasis. Neural crest cells exhibit such coordinated migration, where aberrant motion can lead to fatality or dysfunction of the embryo. Migration involves at least two complementary mechanisms: contact inhibition of locomotion (a repulsive interaction corresponding to a directional change of migration upon contact with a reciprocating cell), and co-attraction (a mutual chemoattraction mechanism). Here, we develop and employ a parameterized discrete element model of neural crest cells, to investigate how these mechanisms contribute to long-range directional migration during development. Motion is characterized using a coherence parameter and the time taken to reach, collectively, a target location. The simulated cell group is shown to switch from a diffusive to a persistent state as the response-rate to co-attraction is increased. Furthermore, the model predicts that when co-attraction is inhibited, neural crest cells can migrate into restrictive regions. Indeed, inhibition of co-attraction in vivo and in vitro leads to cell invasion into restrictive areas, confirming the prediction of the model. This suggests that the interplay between the complementary mechanisms may contribute to guidance of the neural crest. We conclude that directional migration is a system property and does not require action of external chemoattractants