Mathematics of the Integrative
Cancer Biology Program
rsfs.royalsocietypublishing.org
Introduction
Cite this article: Anderson ARA, Tomlin CJ,
Couch J, Gallahan D. 2013 Mathematics of the
Downloaded from https://royalsocietypublishing.org/ on 08 October 2022
Integrative Cancer Biology Program. Interface
Focus 3: 20130023.
http://dx.doi.org/10.1098/rsfs.2013.0023
One contribution of 11 to a Theme Issue
‘Integrated cancer biology models’.
Subject Areas:
computational biology, systems biology
Keywords:
mathematical oncology, National Cancer
Institute, Integrative Cancer Biology Program
Author for correspondence:
Alexander R. A. Anderson
e-mail: alexander.anderson@moffitt.org
† the methodologies to take our understanding to the next level. To add to this
These authors contributed equally to this
study.
Alexander R. A. Anderson1,†, Claire J. Tomlin2,†, Jennifer Couch3
and Dan Gallahan3
1
Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
2
Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, CA 94720, USA
3
National Cancer Institute, Division of Cancer Biology, Rockville, MD 20850, USA
Biological research has long sought the predictability and precision inferred
through mathematical modelling to better understand and explain both
simple and complex natural phenomena. Mathematical insight has been essen-
tial for many advances in ecology, genetics and evolution, but has been less
successful in describing more basic molecular, cellular and disease processes.
While in silico models are critical components of more physically tractable scien-
tific disciplines such as metrology and economics, biology has not fully
embraced or integrated these more quantitative approaches into its research
continuum. Beyond the inherent complexity of biology, there are a variety of
reasons for this lag, including lack of appropriate datasets, ill-defined biological
questions, inappropriate model application and often simple social separation
of the disciplines. Advances in all of these areas are slowly changing this
view to the benefit of modern biology and disease research.
The US National Cancer Institute (NCI) has a simple mission to understand
the biology of cancer in order to better prevent, manage and treat the disease for
the health of the nation and the world. To accomplish this mission, the NCI
supports and conducts a broad range of research enterprises. Indeed, we
have seen positive shifts within the USA in overall cancer incidence and
death rates for some specific cancers.1 Many of these shifts can be attributed
to early detection and healthier lifestyles. Tremendous advances in the treat-
ment of cancer have also been made with probably the most exciting
advance in the area of targeted therapy. Despite this progress, cancer remains
a serious problem with devastating impact at both a personal and societal
level. Certain types of cancer and certain populations have not experienced
the same advances, and resistance is emerging with some of our most promis-
ing drugs. Most sobering is the fact that cancer remains the leading cause of
death worldwide, accounting for 7.6 million deaths (around 13% of all
deaths) in 2008 [1].
The challenge is the complex nature of cancer and the purely reductionist
approach that has advanced the field thus far. It is now well established that
cancer is multiscale involving many processes at the molecular, cellular and
organismal level. At a molecular level, there are a vast collection of mutations
and signalling networks associated with cancer. At a cellular level, we are
beginning to understand the complex milieu of different cell types and inter-
actions that make up the tumour microenvironment and, finally, the many
processes such as inflammation, angiogenesis and the immune response
within the host. All of these processes work in a coordinated fashion to progress
cancer through initiation, metastasis and intervention. Not only is each level a
system unto itself but the systems act across scales in a well-coordinated and
adaptive manner. Modern cancer biology recognizes this and grapples with
complexity of scales is the vast amount of high-dimensional data and infor-
mation that are being generated covering all aspects of a patient’s cancer. The
‘Omic’ revolution is for the first time providing a comprehensive ‘parts list’
for our analysis. The challenge of course is how to make sense of this vast
amount of information and complex interactions. Here is where we turn to
& 2013 The Author(s) Published by the Royal Society. All rights reserved.
 mathematical modelling for the necessary structure and
analytics to provide testable and predictive models to not
only explain but also to probe the various mechanisms
of cancer. Models, while not perfect and by their very nature
wrong [2], are becoming critical and necessary in modern
cancer systems biology as they can be useful both for providing
novel hypotheses and for driving experimentation that leads to
a deeper understanding. Mathematical models are also a great
tool for integrating multiple distinct processes/components of
a system and bridging multiple spatial and temporal scales in
ways that would be impossible for experimentation alone.
Models can be roughly classified as descriptive or mechanistic
and, importantly for this Theme Issue, models can also be used
as a means to integrate data and extract crucial information
from them.
The research community has realized this and has increas-
ingly embraced systems biology and mathematical modelling
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in biomedical research. In 2004, the NCI began the Integrative
Cancer Biology Program (ICBP) with the express purpose of
developing these fields in the area of cancer biology. The ICBP
is a large programme encompassing centres, individual research
grants and educational activities, along with data infrastructure
(http://icbp.nci.nih.gov/). At its core are the Centers for Cancer
Systems Biology, which focus on the analysis of cancer as a com-
plex biological system. The cornerstone of the programme is the
development and implementation of mathematical and compu-
tational models of processes relevant to cancer prevention,
diagnostics and therapeutics. The integration of experimental
biology with mathematical modelling leads to new insights in
cancer biology and innovative approaches to the management
of cancer. The programme brings clinical and basic cancer
researchers together with researchers from mathematics, phy-
sics, information technology, imaging sciences and computer
science to work on key questions in cancer biology. The individ-
ual centres work both as multi-discipline research teams and as
collaborative units in an overall consortium. The centres cover a
broad range of issues in cancer biology from (epi)-genetics and
signalling networks to cellular biology and clinical issues.
The biological components are complemented by mathe-
matical and computational modelling. While always present,
throughout the life of the ICBP the importance of modelling
has steadily increased with both novel approaches and appli-
cations being developed hand in hand with emerging
experimental techniques and data acquisition. As members of
this programme, we began to see a need to bring all of the
theoreticians together to discuss our techniques and results
and how best to apply (and/or integrate) them to the diverse
datasets that were being generated.
This Theme Issue reflects the results of a series of work-
shops that began in Berkeley, CA, in October 2010 and
finished in Tampa, FL, in March 2012, chaired by Claire
Tomlin (UC Berkeley) and Alexander Anderson (Moffitt).
The mathematics of the ICBP workshops brought together
all of the mathematical and computational modellers across
the 12 centres to galvanize a community that was already
developing: mathematical oncology [3]. As part of the work-
shop participation, we asked each centre to provide a list of
key questions that it considered critical to this new commu-
nity. While there were many, some unifying questions
emerged (Box 1).
In addition to these questions, we saw some excellent pre-
sentations highlighting novel approaches to address them,
which led us to ask for possible contributions to this Theme
2
Box 1.
rsfs.royalsocietypublishing.org
(i) How can we deal with the multi-scale nature of
cancer?
(ii) How can we infer signalling networks from static
and dynamic data?
(iii) How do we integrate multiple distinct datasets
into a useful predictive model?
(iv) How does intratumour heterogeneity propagate
both spatially and temporally?
Interface Focus 3: 20130023
(v) How do we effectively treat a heterogeneous
tumour?
(vi) Can we exploit the dialogue between tumour and
microenvironment therapeutically?
(vii) What role does cooperation play in tumour
prevention, progression and resistance to
treatment?
(viii) How can we design experiments to better facilitate
mathematical and computational models?
Issue of Interface Focus; from the initial 40 we obtained, we ulti-
mately selected 10. These papers cover a diverse spectrum of
both modelling techniques and application scales. Methods
which are based on data clustering, segmentation and statisti-
cal regression methods have been used to organize and
understand large biological datasets: the methods in Zhu
et al. [4] use these to help pinpoint the vascular structures
within breast cancer tumours; Gevaert et al. [5] used such
methods in their tool AMARETTO to connect cancer drivers
with their downstream targets. Yet other methods deal with
clever ways to constrain parameter uncertainty: the paper
by Hagen et al. [6] demonstrates that optimal experiment
design may be used to achieve quantifiably accurate par-
ameter estimation. Information theoretic and statistical
methods for inferring and understanding biological pathways
have found great promise in cancer systems biology: the paper
by Jang et al. [7] demonstrates hARACNe, a tool based on the
data-processing inequality from information theory and its
use in inferring transcriptional regulatory networks; and the
paper by Sachs et al. [8] demonstrates how perturbations com-
bined with generalized Bayesian networks can be very
effective in learning network structure. Differential
equation-based models are ideal for capturing both spatial
and temporal dynamics and can be used in a modular-like
manner to connect distinct processes and scales, employed
here by Wilkie & Hahnfeldt [9] to analyse the possible causa-
tive mechanisms of cancer escape from immune-induced
dormancy. Parmar et al. [10] used a modular approach that
incorporates the interaction of three cellular systems:
the unfolded protein response, autophagy and apoptosis to
better understand anti-oestrogen resistance. Single-cell-based
models are ideal for examining interactions and characterizing
the heterogeneous nature of tumours: Gallaher & Anderson
[11] use an off-lattice single-cell-based model to examine how
traits, such as proliferation and migration, are inherited by
cells and alter the spatial and temporal heterogeneity of a
growing tumour; Chang et al. [12] use a single-cell-based
model to examine interactions between co-migrating tumour
 and stromal cells to study the emergence of collective move-
ment. Finally, Basanta & Anderson [13] contribute the only
Endnote 3
1
Surveillance, Epidemiology, and End Results (SEER) Program (www.

review to this Theme Issue on the importance of viewing
cancer from an ecological perspective. Using evolutionary
game theory and cellular automata, they consider cancer as a
disruption of the complex balance of many interacting cellular
and microenvironmental elements in a specific organ.
rsfs.royalsocietypublishing.org
seer.cancer.gov). SEER*Stat Database: Incidence—SEER 9 Regs Research
Data, November 2011 Sub (1973–2010). Katrina/Rita Population
Adjustment—Linked To County Attributes—Total U.S., 1969–2010
Counties, National Cancer Institute, DCCPS, Surveillance Research Pro-
gram, Surveillance Systems Branch, released April 2013, based on the
November 2012 submission.

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