Exploiting evolution to treat drug resistance: Combination therapy and the double bind

Although many anti cancer therapies are successful in killing a large percentage of tumour cells when initially administered, the evolutionary dynamics underpinning tumour progression mean that often resistance is an inevitable outcome, allowing for new tumour phenotypes to emerge that are unhindered by the therapy. Research in the field of ecology suggests that an evolutionary double bind could be an effective way to treat tumours. In an evolutionary double bind two therapies are used in combination such that evolving resistance to one leaves individuals more susceptible to the other. In this paper we present a general evolutionary game theory model of a double bind to study the effect that such approach would have in cancer. Furthermore we use this mathematical framework to understand recent experimental results that suggest a synergistic effect between a p53 cancer vaccine and chemotherapy. Our model recapitulates the experimental data and provides an explanation for its effectiveness based on the commensalistic relationship between the tumour phenotypes

The impact of cellular characteristics on the evolution of shape homeostasis

The importance of individual cells in a developing multicellular organism is well known but precisely how the individual cellular characteristics of those cells collectively drive the emergence of robust, homeostatic structures is less well understood. For example cell communication via a diffusible factor allows for information to travel across large distances within the population, and cell polarisation makes it possible to form structures with a particular orientation, but how do these processes interact to produce a more robust and regulated structure? In this study we investigate the ability of cells with different cellular characteristics to grow and maintain homeostatic structures. We do this in the context of an individual-based model where cell behaviour is driven by an intra-cellular network that determines the cell phenotype. More precisely, we investigated evolution with 96 different permutations of our model, where cell motility, cell death, long-range growth factor (LGF), short-range growth factor (SGF) and cell polarisation were either present or absent. The results show that LGF has the largest positive impact on the fitness of the evolved solutions. SGF and polarisation also contribute, but all other capabilities essentially increase the search space, effectively making it more difficult to achieve a solution. By perturbing the evolved solutions, we found that they are highly robust to both mutations and wounding. In addition, we observed that by evolving solutions in more unstable environments they produce structures that were more robust and adaptive. In conclusion, our results suggest that robust collective behaviour is most likely to evolve when cells are endowed with long range communication, cell polarisation, and selection pressure from an unstable environment

A mathematical model of tumor self-seeding reveals secondary metastatic deposits as drivers of primary tumor growth

Two models of circulating tumor cell (CTC) dynamics have been proposed to explain the phenomenon of tumor 'self-seeding', whereby CTCs repopulate the primary tumor and accelerate growth: Primary Seeding, where cells from a primary tumor shed into the vasculature and return back to the primary themselves; and Secondary Seeding, where cells from the primary first metastasize in a secondary tissue and form microscopic secondary deposits, which then shed cells into the vasculature returning to the primary. These two models are difficult to distinguish experimentally, yet the differences between them is of great importance to both our understanding of the metastatic process and also for designing methods of intervention. Therefore we developed a mathematical model to test the relative likelihood of these two phenomena in the subset of tumours whose shed CTCs first encounter the lung capillary bed, and show that Secondary Seeding is several orders of magnitude more likely than Primary seeding. We suggest how this difference could affect tumour evolution, progression and therapy, and propose several possible methods of experimental validation.Comment: 20 pages, 4 figure

Cloud-radiative impacts on the tropical Indian Ocean associated with the evolution of ‘monsoon breaks'

A detailed diagnostic analysis of a suite of observed datasets was carried out with a view to understand the importance of cloud-radiative effects on the evolution of prolonged ‘monsoon breaks’ over the Indian region. The study particularly focuses on the role of clouds in affecting the sub-seasonal/intra-seasonal variability of sea surface temperature (SST) and atmospheric convection in the equatorial and south-eastern tropical Indian Ocean (SETIO) during monsoon-break transitions. A characteristic feature of the monsoon-break evolution is the appearance of suppressed convection over the SETIO region nearly 7–10 days prior to the commencement of a break spell over India. It is seen from the present analysis that the lack of cloud cover over the SETIO during the 'pre-break' phase leads to significant warming of the tropical Indian Ocean due to strong solar insolation at the surface. During the ‘pre-break’ phase, the net cloud-radiative forcing (NETCRF) at the surface is found to be typically around − 30 Wm−2 and the mean SST in the SETIO is about 29.3 °C. Following the transition to a monsoon-break phase, the cloud amount increases by about 25% over the SETIO region in association with intensified convection. The NETCRF at the surface over the SETIO averaged during the 'break' phase is found to be about − 60 Wm−2 (i.e. a change of about − 30 Wm−2 from the ‘pre-break’ phase). Consistent with the above change in the NETCRF, the SST in the SETIO shows a cooling of about 0.7 °C, although the mean SSTs during the ‘break’ phase remain as high as 28.6 °C. On the basis of the findings from this study, it is suggested that the SST warming during the ‘pre-break’ phase plays a key role in maintaining high SST and allows sustained convection to occur over the SETIO during prolonged monsoon breaks

Influence of wildland fire on surface runoff from a hillslope

Surface runoff from three adjacent hillslope plots, unbumt or subjected to light or moderate prescribed burns, was monitored over a four-year period. Al1 plots initially bore Ulex scmb. In the fust year, runoff from the unburnt plot was about 3.5% of rainfail, while that from the bumt plots was between 5.2 and 6.6% of rainfail. Runoff from the burnt plots graduaily dropped over the study penod, and we estimate that preburn values are reattained within four to five years (corresponding to the time required for re-establishment of the vegetation cover). The water repellency of the soil was not appreciably increased by either light or moderate bums, indicating that wildfire-induced increases in runoff in this region are due largely to reduced interception as a result of the destruction of vegetation. Finaily, although buming caused clear relative increases in mnoff, the absolute increases were small (2 - 3% of rainfall), suggesting that wildfire-induced increases in runoff are unlikely to have major effects on the flow regimes of receiving nvers. The estimated postfire increases in infiltration, on the other hand, were much more marked, and it is possible that wildfire-induced increases in subsurface flow have important effects on watershed hydrology

Investigating prostate cancer tumour-stroma interactions - clinical and biological insights from an evolutionary game

BACKGROUND: Tumours are made up of a mixed population of different types of cells that include normal structures as well as ones associated with the malignancy, and there are multiple interactions between the malignant cells and the local microenvironment. These intercellular interactions, modulated by the microenvironment, effect tumour progression and represent a largely under appreciated therapeutic target. We use observations of primary tumor biology from prostate cancer to extrapolate a mathematical model: specifically; it has been observed that in prostate cancer three disparate cellular outcomes predominate: (i) the tumour remains well differentiated and clinically indolent - in this case the local stromal cells may act to restrain the growth of the cancer; (ii) early in its genesis the tumour acquires a highly malignant phenotype, growing rapidly and displacing the original stromal population (often referred to as small cell prostate cancer) - these less common aggressive tumours are relatively independent of the local microenvironment; and, (iii) the tumour co-opts the local stroma - taking on a classic stromagenic phenotype where interactions with the local microenvironment are critical to the cancer growth. METHODS: We present an evolutionary game theoretical construct that models the influence of tumour-stroma interactions in driving these outcomes. We consider three characteristic and distinct cellular populations: stromal cells, tumour cells that are self-reliant in terms of microenvironmental factors and tumour cells that depend on the environment for resources but can also co-opt stroma. 
RESULTS: Using evolutionary game theory we explore a number of different scenarios that elucidate the impact of tumour-stromal interactions on the dynamics of prostate cancer growth and progression and how different treatments in the metastatic setting can affect different types of tumors.
CONCLUSIONS: The tumour microenvironment plays a crucial role selecting the traits of the tumour cells that will determine prostate cancer progression. Equally important, treatments like hormone therapy affect the selection of these cancer phenotypes making it very important to understand how they impact prostate cancer’s somatic evolution