Integration of Molecular Signaling into Multiscale Modeling of Cancer - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 376

set of pre-defined biologically inspired computational rules. Tightly coupling and
iteratively refining these roles at all stages of model development with in vitro or in
vivo experiments is important [ 14 ]. An ABM produces emergent behavior that
arises from the behavior and interactions evolving at a cellular level. To date, the
ABM has been used to simulate a variety of cancer aspects, such as somatic
evolution in tumorigenesis [ 15 , 16 ], the growth dynamics of multicellular tumor
spheroids [ 17 , 18 ], and cancer cell invasion [ 19 , 20 ]. In this chapter, we focus on
the introduction of the design and development of a specific type of ABM, i.e.,
molecular signaling incorporated multiscale ABM. This type of ABM is able to
address the role of diversity in cell populations and also within each individual
cell, and thus have the capacity to explore the relationship between molecular
signaling properties and upper level cancer behavior.
2 Modeling Approach
Cancer is a complex disease involving a series of irreversible genomic changes
that affect intrinsic cellular programs [ 2 ]. Wet-lab cancer researchers probably do
not appreciate a model which misses correlations of molecular-level alterations
with cancer cell properties, because it is essentially the aberration of signaling
pathways that contributes to the initiation and progression of cancer [ 21 ]. Cancer is
also a context-dependent disease [ 22 ], implicating that its progression behaviors
depend on the microenvironment where the activities of cancer cells take place.
More precisely, cancer cells bi-directionally communicate with their microenvi-
ronment, not only responding to various external cues but also impacting their
surroundings, e.g., by producing various signals and degrading the neighboring
tissue through proteases [ 23 ]. ABM is of particular interest to cancer modelers
because, as we will introduce below, it allows researchers to explore how cancer
growth and invasion properties (due to cell proliferation and migration) emerge as
a result of individual dynamics, including cell-cell and cell-environment inter-
actions and intracellular signaling of individual cells.
In the following, the design concept and development of the most recent
molecular signaling-incorporated multiscale ABMs will be discussed. Special
focus is given to the demonstration of how these two scales are explicitly linked by
what algorithm to determine cell phenotypic transitions upon what molecular
changes.
2.1 EGFR Signaling and Cellular Phenotypic Transition
A set of molecular-multicellular ABMs within brain tumors and non-small cell lung
cancer (NSCLC) have been developed. These models (as reviewed in [ 4 , 12 , 24 ])