Integration of Molecular Signaling into Multiscale Modeling of Cancer - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 379

2.1.4 Modeling Examples
A simplified representation of the EGFR signaling pathway and the aforemen-
tioned molecularly-driven cellular phenotype decision algorithm were first applied
to the investigation of brain tumor growth in a 2D environment [ 33 , 34 ]. The
models examined how the molecular profile of each individual glioma cell impacts
the cell's phenotypic switch, and how such context-specific single-cell activities
potentially affect the dynamics of the entire tumor system. In particular, the
models found that increasing the EGFR density per cell results in an acceleration
of the entire tumor system's spatiotemporal expansion dynamics [ 34 ], a finding
that is in good agreement with published experimental data [ 35 ]. To simulate brain
tumor growth in a more realistic microenvironment, a 3D model was developed
[ 36 ], where a simplified cell-cycle description at the sub-cellular scale based on
[ 37 ] was added to molecular layer. The simulation results not only confirmed the
impact of regulation of EGFR signaling on tumor behavior (both on the single cell
and multi-cellular level), but also indicated that over time, proliferative and
migratory cell populations oscillate and have a direct effect on the entire spatio-
temporal tumor expansion pattern. A recent extension study [ 38 ] further studied
the emergence of heterogeneous tumor cell clones through introducing an element
of genetic instability and analyzed how heterogeneity impacts brain tumor pro-
gression patterns. Simulation results showed that cell clones with higher EGFR
density were comprised of a larger migratory fraction and smaller proliferative and
quiescent fractions, which corresponds well with reported experimental data [ 39 ].
EGFR also plays an important role in progression and metastasis of NSCLC.
Can the same modeling method be applied to NSCLC as well? A 2D model with a
revised EGF-induced, EGFR-mediated pathway specific to NSCLC was developed
to quantitatively understand the relationship between extrinsic chemotactic stimuli,
the underlying properties of signaling networks, and the cellular biological
responses they trigger in NSCLC from a systemic view [ 40 ]. In addition to con-
firming the experimentally known fact that increasing the amount of available
growth factors leads to a spatially more aggressive cancer system [ 41 , 42 ], the
model found that in the cancer cell closest to the nutrient source, a minimal increase
in EGF concentration can temporarily abolish its proliferative phenotype. More
recently, the model was extended to a 3D case in which both EGF and transforming
growth factor b (TGFb) and their interplay were taken into account [ 43 ]. This
physiologically and clinically motivated extension of the NSCLC modeling plat-
form allowed for investigating how the effects of individual and combinatorial
change in EGF and TGFb concentrations at the molecular level alter tumor growth
dynamics (including tumor volume and expansion rate) on the multi-cellular level.
A particular region of tumor system stability, generated by unique pairs of EGF and
TGFb concentration variations, was discovered. Figure 2 shows the simulation
results from changing EGF and TGFb concentrations both simultaneously and
asynchronously. As can be seen, the common stable phenotypic region is generated
by [2-7]-fold variation of EGF and [0.3-3]-fold variation of TGFb. This result
indicates that when the variation-pair of EGF and TGFb concentrations occurred