Biology subjects

Cleri, F.

Publications and source records attributed to Cleri, F..

2 recordsLinked to original sources

bioRxiv2018

Agent-based model of multicellular tumor spheroid evolution including cell metabolism

Computational models aiming at the spatio-temporal description of cancer evolution are a suitable framework for testing biological hypotheses from experimental data, and generating new ones. Building on our recent work [J Theor Biol 389, 146-158 (2016)] we develop a 3D agent-based model, capable of tracking hundreds of thousands of interacting cells, over time scales ranging from seconds to years. Cell dynamics is driven by a Monte Carlo solver, incorporating partial differential equations to describe chemical pathways and the activation/repression of \"genes\", leading to the up- or down-regulation of specific cell markers. Each cell-agent of different kind (stem, cancer, stromal etc.) runs through its cycle, undergoes division, can exit to a dormant, senescent, necrotic state, or apoptosis, according to the inputs from their systemic network. The basic network at this stage describes glucose/oxygen/ATP cycling, and can be readily extended to cancer-cell specific markers. Eventual accumulation of chemical/radiation damage to each cells DNA is described by a Markov chain of internal states, and by a damage-repair network, whose evolution is linked to the cell systemic network. Aimed at a direct comparison with experiments of tumorsphere growth from stem cells, the present model will allow to quantitatively study the role of transcription factors involved in the reprogramming and variable radio-resistance of simulated cancer-stem cells, evolving in a realistic computer simulation of a growing multicellular tumorsphere.

biophysics↗

bioRxiv2018

Mechanical evolution of DNA double-strand breaks in the nucleosome

Double strand breaks in the DNA backbone are the most lethal type of defect that can be induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the potentially large differences in the outcomes of damage between free and nucleosomal DNA, leading to corresponding differences in damage repair capability. We performed microsecond-length molecular dynamics computer simulations of nucleosomes including double-strand breaks (DSB) at various sites, to characterize the early stages of the evolution of this important DNA lesion right after its formation. We find that all DSB configurations tend to remain compact, with only the terminal bases interacting with histone proteins; the interacting molecular structures are studied by looking at the essential dynamics of the relevant DNA and histone fragments, and compared to the intact nucleosome, thus exposing key features of the interactions. Moreover, we show that the broken DNA ends at the DSB must overcome a free-energy barrier to detach from the nucleosome core, as measured by means of umbrella sampling of the potential of mean force. Finally, by using state-of-the-art calculation of the covariant mechanical stress at the molecular scale, we demonstrate that, depending on the DNA-core separation distance, the coupled bending and torsional stress stored in the detached DNA can force the free end to either stick back to the nucleosome core surface, or to open up straight, thus making it accessible to damage signalization proteins.

biophysics↗