Cooperation between Noncanonical Ras Network Mutations in Cancer

Edward C Stites, Paul C Trampont, Lisa B Haney, Scott F Walk, Kodi S Ravichandran

doi: http://dx.doi.org/10.1101/004846

Cancer develops after the acquisition of a collection of mutations that together create the ‘cancer phenotype’. How collections of mutations work together within a cell, and whether there is selection for certain combinations of mutations, are not well understood. Using a Ras signaling network mathematical model we tested potential synergistic combinations within the Ras network. Intriguingly, our modeling, including a “computational random mutagenesis” approach, and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the effects of mutations in multiple other components of the Ras pathway, including weakly activating, noncanonical, Ras mutants. Since conventional wisdom holds that mutations within the same pathway do not co-occur, it was surprising that modeling and experiments both suggested a functional benefit for co-occurring Ras pathway mutations. Furthermore, we analyzed >3900 sequenced cancer specimens from the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) and we uncovered an increased rate of co-occurrence between mutations the model predicted could display synergy. Overall, these data suggest that selective combinations of Ras pathway mutations could serve the role of cancer “driver”. More generally, this work presents a mechanism by which the context created by one mutation influences the evolutionary trajectories of cancer development, and this work suggests that mutations that result in “network instability” may promote cancer in a manner analogous to genomic instability.

Link: http://www.biorxiv.org/content/early/2014/05/06/004846

Bridging scales in cancer progression: Mapping genotype to phenotype using neural networks

Philip Gerlee, Eunjung Kim, Alexander R.A. Anderson

(Submitted on 28 Apr 2014)

In this review we summarize our recent efforts in trying to understand the role of heterogeneity in cancer progression by using neural networks to characterise different aspects of the mapping from a cancer cells genotype and environment to its phenotype. Our central premise is that cancer is an evolving system subject to mutation and selection, and the primary conduit for these processes to occur is the cancer cell whose behaviour is regulated on multiple biological scales. The selection pressure is mainly driven by the microenvironment that the tumour is growing in and this acts directly upon the cell phenotype. In turn, the phenotype is driven by the intracellular pathways that are regulated by the genotype. Integrating all of these processes is a massive undertaking and requires bridging many biological scales (i.e. genotype, pathway, phenotype and environment) that we will only scratch the surface of in this review. We will focus on models that use neural networks as a means of connecting these different biological scales, since they allow us to easily create heterogeneity for selection to act upon and importantly this heterogeneity can be implemented at different biological scales. More specifically, we consider three different neural networks that bridge different aspects of these scales and the dialogue with the micro-environment, (i) the impact of the micro-environment on evolutionary dynamics, (ii) the mapping from genotype to phenotype under drug-induced perturbations and (iii) pathway activity in both normal and cancer cells under different micro-environmental conditions.

link: http://arxiv.org/abs/1404.7108

Niche inheritance: a cooperative pathway to enhance cancer cell fitness though ecosystem engineering

Kimberline R. Yang, Steven Mooney, Jelani C. Zarif, Donald S. Coffey, Russell S. Taichman, Kenneth J. Pienta

(Submitted on 28 Mar 2014)

Cancer cells can be described as an invasive species that is able to establish itself in a new environment. The concept of niche construction can be utilized to describe the process by which cancer cells terraform their environment, thereby engineering an ecosystem that promotes the genetic fitness of the species. Ecological dispersion theory can then be utilized to describe and model the steps and barriers involved in a successful diaspora as the cancer cells leave the original host organ and migrate to new host organs to successfully establish a new metastatic community. These ecological concepts can be further utilized to define new diagnostic and therapeutic areas for lethal cancers.

link: http://arxiv.org/abs/1403.7413 

A continuous model of osteocyte generation in bone matrix

A continuous model of osteocyte generation in bone matrix 

Author: P R Buenzli


Abstract:

The formation of new bone involves both the deposition of bone matrix by cells called osteoblasts, and the formation of a network of cells embedded within the bone matrix, called osteocytes. Osteocytes derive from osteoblasts that become buried in bone matrix during bone deposition. There has been a growing interest in osteocytes in recent years with the realisation that these cells are essential to the detection of micro-damage in bone, and that they participate in the orchestration of local bone renewal. However, the generation of osteocytes is a complex process that remains incompletely understood. Whilst osteoblast burial determines the density of osteocytes, the expanding network of osteocytes regulates in turn osteoblast activity and osteoblast burial through their interconnected cell processes. In this contribution, a spatiotemporal continuous model is proposed to investigate the osteoblast-to- osteocyte transition. The model elucidates the interplays between matrix secretory rate, rate of entrapment, and curvature of the bone substrate in determining the density of osteocytes in the new bone matrix. We find that the density of osteocytes generated at the moving deposition front depends solely on the ratio of the instantaneous burial rate and matrix secretory rate. It is remarkably independent of osteoblast density and substrate curvature. This mathematical result is used with experimental measurements of osteocyte lacuna distributions in a human cortical bone sample to determine for the first time the rate of burial of osteoblasts in bone matrix. Our results suggest that in the bone specimen analysed: (i) burial rate decreases during osteonal infilling, and (ii) the control of osteoblast burial by osteocytes is likely to emanate as a collective signal from a large group of osteocytes, rather than from the osteocytes closest to the bone deposition front.

From arXiv: http://arxiv-web3.library.cornell.edu/abs/1403.2526

A tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Christopher Dennis McFarland, Leonid A Mirny, Kirill S Korolev

doi: 10.1101/003053

Abstract

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few ‘driver’ mutations occur alongside thousands of random ‘passenger’ mutations––a natural consequence of cancer's elevated mutation rate. Some passengers can be deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression that is described by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers meltdown. We find support for the model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to rationalize successes and failures of different treatment strategies. We find that a tumor’s load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by both current and future therapies.

From the bioRxiv :  http://biorxiv.org/content/early/2014/02/26/003053

Cancer-driven dynamics of immune cells in a microfluidic environment

Elena Agliari, Elena Biselli, Adele De Ninno, Giovanna Schiavoni, Lucia Gabriele, Anna Gerardino, Fabrizio Mattei, Adriano Barra, Luca Businaro

(Submitted on 3 Feb 2014)

Scope of the present work is to frame into a rigorous, quantitative scaffold - stemmed from stochastic process theory - two sets of experiments designed to infer the spontaneous organization of leukocytes against cancer cells, namely mice splenocytes vs. B16 mouse tumor cells, and embedded in an "ad hoc" microfluidic environment developed on a LabOnChip technology. In the former, splenocytes from knocked out (KO) mice engineered to silence the transcription factor IRF-8, crucial for the development and function of several immune populations, were used. In this case lymphocytes and cancer cells exhibited a poor reciprocal exchange, resulting in the inability of coordinating or mounting an effective immune response against melanoma. In the second class of tests, wild type (WT) splenocytes were able to interact with and to coordinate a response against the tumor cells through physical interaction. The environment where cells moved was built of by two different chambers, containing respectively melanoma cells and splenocytes, connected by capillary migration channels allowing leucocytes to migrate from their chamber toward the melanoma one. We collected and analyzed data on the motility of the cells and found that the first ensemble of IRF-8 KO cells performed pure uncorrelated random walks, while WT splenocytes were able to make singular drifted random walks, that, averaged over the ensemble of cells, collapsed on a straight ballistic motion for the system as a whole. At a finer level of investigation, we found that IRF-8 KO splenocytes moved rather uniformly since their step lengths were exponentially distributed, while WT counterpart displayed a qualitatively broader motion as their step lengths along the direction of the melanoma were log-normally distributed.

 http://arxiv.org/abs/1402.0451

Evolutionary dynamics of shared niche construction

Philip Gerlee, Alexander R.A. Anderson

(Submitted on 4 Feb 2014)

Many species engage in niche construction that ultimately leads to an increase in the carrying capacity of the population. We have investigated how the specificity of this behaviour affects evolutionary dynamics using a set of coupled logistic equations, where the carrying capacity of each genotype consists of two components: an intrinsic part and a contribution from all genotypes present in the population. The relative contribution of the two components is controlled by a specificity parameter $\gamma$, and we show that the ability of a mutant to invade a resident population depends strongly on this parameter. When the carrying capacity is intrinsic, selection is almost exclusively for mutants with higher carrying capacity, while a shared carrying capacity yields selection purely on growth rate. This result has important implications for our understanding of niche construction, in particular the evolutionary dynamics of tumor growth.

on the arXiv:  http://arxiv.org/abs/1402.0757
or the bioRxiv: http://www.biorxiv.org/content/early/2014/02/05/002378