Investigating the relation between stochastic differentiation and homeostasis in intestinal crypts via multiscale modeling

Alex Graudenzi, Giulio Caravagna, Giovanni De Matteis, Marco Antoniotti

doi: 10.1101/000927

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ABSTRACT

Colorectal tumors originate and develop within intestinal crypts. Even though some of the essential phenomena that characterize crypt structure and dynamics have been effectively described in the past, the relation between the differentiation process and the overall crypt homeostasis is still partially understood. We here investigate this relation and other important biological phenomena by introducing a novel multiscale model that combines a morphological description of the crypt with a gene regulation model: the emergent dynamical behavior of the underlying gene regulatory network drives cell growth and differentiation processes, linking the two distinct spatio-temporal levels. The model relies on a few a priori assumptions, yet accounting for several key processes related to crypt functioning, such as: dynamic gene activation patterns, stochastic differentiation, signaling pathways ruling cell adhesion properties, cell displacement, cell growth, mitosis, apoptosis and the presence of biological noise. We show that this modeling approach captures the major dynamical phenomena that characterize the regular physiology of crypts, such as cell sorting, coordinate migration, dynamic turnover, stem cell niche maintenance and clonal expansion. All in all, the model suggests that the process of stochastic differentiation might be sufficient to drive the crypt to homeostasis, under certain crypt configurations. Besides, our approach allows to make precise quantitative inferences that, when possible, were matched to the current biological knowledge and it permits to investigate the role of gene-level perturbations, with reference to cancer development. We also remark the theoretical framework is general and may applied to different tissues, organs or organisms.

link: http://www.biorxiv.org/content/early/2013/11/25/000927

A multi-phenotypic cancer model with cell plasticity

Da Zhou, Yue Wang, Bin Wu

(Submitted on 25 Nov 2013)

The conventional cancer stem cell (CSC) theory indicates a hierarchy of CSCs and non-stem cancer cells (NSCCs), that is, CSCs can differentiate into NSCCs but not vice versa. However, an alternative paradigm of CSC theory with reversible cell plasticity among cancer cells has received much attention very recently. Here we present a generalized multi-phenotypic cancer model by integrating cell plasticity with the conventional hierarchical structure of cancer cells. Based on our model, we theoretically explain the universality of the phenotypic equilibrium phenomena reported in various cancer cell lines. By applying our model to concrete biological examples with real experimental data, we show that cancer cell plasticity plays an essential role in transient regulation of cancer heterogeneity. Our work may pave the way for modeling and analyzing the cell population dynamics with cell plasticity.

http://arxiv.org/abs/1311.6222

The age specific incidence anomaly suggests that cancers originate during development

James P. Brody

(Submitted on 31 Oct 2013)

Cancers are caused by the accumulation of genetic alterations. Since this accumulation takes time, the incidence of most cancers is thought to increase exponentially with age. However, careful measurements of the age-specific incidence shows that the specific incidence for many forms of cancer rises with age to a maximum, then decreases. This decrease in the age-specific incidence with age is an anomaly. Understanding this anomaly should lead to a better understanding of how tumors develop and grow. Here I derive the shape of the age-specific incidence, showing that it should follow the shape of a Weibull distribution. Measurements indicate that the age-specific incidence for colon cancer does indeed follow a Weibull distribution. This analysis leads to the interpretation that for colon cancer two sub-populations exist in the general population: a susceptible population and an immune population. Colon tumors will only occur in the susceptible population. This analysis is consistent with the developmental origins of disease hypothesis and generalizable to many other common forms of cancer.

link: http://arxiv.org/abs/1310.8619