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AACR 2007 American Association for Cancer Research
Late breaking poster: LB-257
Presented April 17, 2007, by Mason Vail.
 

Virtual Tissue Models for Studying Cancer Mechanisms

We have created a computational research platform for studying how alterations of cellular processes lead to cancer, and for high fidelity modeling of development, organization, and function of healthy tissues. In these 3D models, cells, genes, cellular pathways and processes, signaling and gene regulatory networks, and physical parameters are represented in software that grows multicellular virtual tissues that are stable yet dynamic: responsive to stimuli, injury, or mutation.

Our technology provides capabilities that conventional wet-bench approaches do not have: it is possible to measure, monitor, or manipulate the internal state of any cell without disrupting the tissue. Networks of signaling and gene expression and regulation may be examined on a cell-by-cell basis or summarized for the tissue as a whole. The models also serve as high-throughput hypothesis testers for refinement of wet-bench studies.

The platform includes primitives for gene expression, signaling, adhesion, extracellular matrix (ECM), transport and surface binding, secretion, cell cycle, molecular turnover, and apoptosis - many processes that are the basis for cancer [1]. Higher order tissue properties are not specified, but instead emerge from transactions carried out by molecules within and between cells according to rules specified in the physics of the model, resulting in cell division, growth, death, or other actions.

Cell-based in silico modeling is an important part of any comprehensive approach to identify pre-cancerous lesions or target pathways and predict effects of mutations, drug treatments, or physical manipulations on tissue architecture and function, in vivo or in culture. A researcher can easily introduce targeted mutations or gene knock-outs (-ins, -downs), and monitor their effects on subsequent growth, differentiation, organization, and function.

For instance, a virtual epithelium developed on this platform exhibits dynamic turnover through death and sloughing of cells at the apical surface coupled with replenishment from basal cells. As development proceeds, microenvironments are created with conditions suitable for controlling cell behavior, until steady-state, homeostatic balance is reached. Basal cell mutations that promote aberrant division of cells detached from the basement membrane produce aggressive, locally invasive clumps of small, neoplastic virtual cells with diminished keratin, similar to basal cell carcinoma.

 
[1] Vogelstein, B. and Kinzler, K.W. "Cancer genes and the pathways they control", Nature Medicine 10:789-799, 2004. Pub Med Reference


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