A

crucial part of
any mathematicians
lab - the blackboard!
Dusty, messy
brainstorming
fun!

Integrate: to combine one thing with another so

that they become a whole
That is the definition of integrate and the key word that unifies mathematics with oncology. It is appropriate on more than one level, as the power of
mathematical modeling is its ability to integrate multiple interacting variables at once and predict in a dynamic manner how these variables change in
space and time. Integration is not the antithesis of reductionism
but is in fact a means to bridge the perspectives of reductionism
and holism, as the component parts are vitally important but how
they interact to produce the emergent whole is also critical.

Cancer is a complex, multiscale process, in which genetic

mutations occurring at a subcellular level manifest themselves as
functional changes at the cellular and tissue scale. The multiscale
nature of cancer requires mathematical modeling approaches of a
similar nature - within the IMO we have been developing a suite of
mathematical and computational models that allow us to consider
each of these scales in detail as well as bridge them. We are open
minded when it comes to which theoretical tools should be used,
be they individual, hybrid, or purely continuum based, in order to
better capture the complexity of cancer. Gene Protein Pathway Cell Tissue Organ Organism

1
 Contact
Dr. Alexander R. A. Anderson
us!
Integrated Mathematical Oncology
Yvette Mieles (Assistant)
H. Lee Moffitt Cancer Center & Research Institute
Email: yvette.mieles@moffitt.org
12902 Magnolia Drive, MRC 3 West
Phone: +1-813-745-4316
Tampa, Florida, 33612.
Fax: +1-813-745-6497
Email: Alexander.Anderson@moffitt.org
Web: labpages.moffitt.org/andersona

2
CONTENTS ISSUE 1
IMO 1, 4
DOES “CURING” CANCER KILL PATIENTS? 5
MEET THE FACULTY 6
MEET THE POSTDOCS 7
ECOLOGY AND EVOLUTION OF CANCER 8-9
BIG CITY SLUMS AND TUMOR INVASION 10
WORKSHOPS 11
IMO SEMINARS 12
BOOK BY IMO MEMBERS 13
COMPUTATIONAL IMAGES FROM IMO 14
CAN YOU BUILD ME A MODEL PLEASE? 15
LAST WORD 16

3

IMO - Continued
This bridging nature of mathematical models is also important for
understanding how the different biological scales of cancer impact upon
one another. Mutations at the molecular scale affect protein formation
which effect signaling pathways which modulate cell behavior that
transforms the tissue. This complex multiscale process can be broken
down into smaller units that are more amenable to both experimental and
theoretical approaches. Whilst its clear that the M in IMO is a fundamental
tool to bridge the different scales of cancer, it also has the power to make
predictions and generate hypothesis. However, we need some means to
validate these mathematical models and to test the predictions they make.
This will require  sophisticated imaging techniques and potentially new
experimental & clinical protocols. As such IMO, is a truly interdisciplinary
group of scientists incorporating experts in the field of experimental
biology, mathematics, computer science, imaging, clinical science and
visualization.
One of our major goals is to begin to focus on specific cancers and
their treatment, and develop in silico models both as a compliment to in
vitro and in vivo models but also as a means to bridge them.
There is an unspoken void between in vitro and in
vivo models and between in vivo and the
clinic. In silico models have the power to
link these approaches and in doing
so can give some insight into the
processes that translate well
between them and those that
don’t.
Focussing on a specific
cancers means we can also
consider specific treatments. To this
end we have began to develop specific
models of cancers such as breast, prostate,
melanoma, and myeloma. These models
incorporate specific cellular and microenvironmental properties
of these cancers as well as structural and signaling aspects. Treatment is
a natural place for IMO to play a role in because by its very definition
treatment needs to consider a multitude of interacting variables and what
happens to them once they are perturbed. We ultimately see in silico
models as a pre-treatment protocol to suggest the best therapeutic
regime or to indicate which should be avoided. They can also be
considered as an adjuvant in terms of adjusting treatment in a more
dynamic manner, where the current patient state determines the therapy
i.e. an adaptive therapy. Patient specific treatments should be a natural
byproduct of properly parameterized in silico models, since changes in
parameters can lead to different outcomes. Understanding where the
current state of a patient is in the “parameter space” will allow us to
predict how the cancer will progress and therefore how best to treat it.
This is very much in line with the Total Cancer Care program at Moffitt.
It is important to understand that because cancer is a complex
dynamic process does not mean that we cannot fully understand it. In fact
many complex systems are driven by relatively simple laws, therefore the
in silico models IMO develop will not only be specific but must also be
general to address the fundamental underlying mechanisms of cancer
initiation, progression and control. Mathematicians are ideally suited to
this task as they have a long history in discovering the laws of nature
(physics, chemistry etc). There may very well be fundamental laws of
cancer, that if defined and formalized would change completely how we
4
understand and treat cancer as we do today. We are certainly on the right
road to uncovering such laws and one unifying law that must be
integrated into our fundamental understanding of cancer is evolution.
It is generally well accepted that cancer is a genetic disease driven
by mutations in key genes that lead to uncontrolled growth and abnormal
cell behavior. However, the fact that the tumor is an evolving system and
therefore subject to selection pressure and adaptation is largely ignored.
Theoretical models tell us that these evolutionary dynamics are what drive
tumor progression, and treatment resistance. Three other key factors that
also need to be understood within any unifying theory of cancer are
homeostasis, heterogeneity and ecology. Ecology and evolution are
intimately linked as one provides the players and the field and the other
the mechanism by which cancer progresses, this is discussed in more
detail by David Basanta and myself (Page 6). Ultimately all cancers
originate from a cell within an organ or tissue that was functioning
normally i.e. homeostatic. Normal for many cells in this situation is doing
very little, except when there is a need to, such as to occasionally repair a
wound or react to a viral attack. This disruption of homeostasis is often
one of the initiating events in the development of cancer as the normal
control mechanisms of the tissue are damaged or ignored.
Heterogeneity within the tumor cell population is
generally well accepted but is it driven by
genotypic or phenotypic means and
did it emerge or was it always there.
Heterogeneity is certainly
important for treatment
resistance but it may also drive
or be driven by evolution.
Understanding these four key
factors and their interplay in
cancer progression is one of our
goals. Here is one possible scenario
that encapsulates all four of them - the
ecology of a given organ, that is the cells,
chemicals, signaling and structure that define it, all interact to
ensure that homeostasis is maintained. This homeostasis is not static but
dynamic as it reacts to perturbations (such as wounding) to ensure a
return to homeostasis occurs. Natural heterogeneity within the cell
population may allow some cells to escape this homeostatic control easier
than others and with additional (probably genetic insults) a true escape
can occur. This then opens the door to evolution and tumor progression.
Its seems appropriate to end this introductory piece by restating why
IMO was created in the first place, to paraphrase myself: “Cancer is a
dynamic complex multiscale system that can only truly be understood via
the integration of theory and experiments. The goal of IMO is to use such
an integrated approach to better understand, predict and treat cancer.”
Integration really is the key and if we are serious about impacting
treatment that integration must also encapsulate the clinic. The schematic
at the center of this page highlights the multiple scales that different
researchers, involved in cancer research, are gathering data on.
Traditionally the genes to patient jump is made without considering the
scales in between because researchers tend to work within their specific
scale. Using the expertise in the IMO we now have the means to develop
a mechanistic understanding of how these scales connect in cancer and
importantly how changes in one affect the others. As we move forward
this understanding will become critical in the prediction and optimization
of treatment response.
BY SANDY ANDERSON
DOES “CURING” CANCER KILL
PATIENTS? BY ROBERT GATENBY
Patients and politicians increasingly
demand a “cure” for cancer. But controlling the
disease may prove to be a better strategy than
striving to cure it.
A century ago, the German Nobel laureate
Paul Ehrlich introduced into medicine the
concept of “magic bullets” – compounds
engineered to target and kill tumor cells or
disease-causing organisms without affecting
normal cells. The success of antibiotics 50 years
later seemed to validate Ehrlich’s idea. Indeed,
so influential have medicine’s triumphs over
bacteria been that the “war on cancer”
continues to be driven by the assumption that
magic bullets will one day be found for tumor
cells if the search is sufficiently clever and
diligent.
Yet lessons learned in dealing with exotic
species, combined with recent mathematical
models of the evolutionary dynamics of tumors,
indicate that eradicating most cancers may be
impossible. More importantly, trying to do so
could worsen the problem.
In 1854, the year Ehrlich was born, the
diamondback moth was first observed in Illinois.
Within five decades, the moth had spread
throughout North America. It now infests the
Americas, Europe, Asia, and Australia. Attempts
to eradicate it using various chemicals worked
only fleetingly and, in the late 1980’s, biologists
found strains that were resistant to all known
insecticides.
So farmers have had to abandon efforts to
eliminate the moth. Instead, most now apply
insecticides only when infestation exceeds
some threshold level, with the goal of producing
a sustainable and satisfactory crop. Under the
banner of “integrated pest management,”
hundreds of invasive species are now
successfully controlled by strategies that restrict
the pest population growth but do not attempt
to eradicate them
The ability of tumor cells to adapt to a wide
range of environmental conditions, including to
toxic chemicals, is similar to the evolutionary
capacities demonstrated by crop pests and
other invasive species. As in the case of the
Diamondback moth, successful eradication of
disseminated cancer cells is rare. However,
despite the paucity of success, the typical goal
in cancer therapy remains similar to that of
antimicrobial treatments - killing as many tumor
cells as possible under the assumption that this
will, at best, cure the disease and, at worst,
keep the patient alive for as long as possible.
To be sure, some types of cancer – for
example, Hodgkin’s lymphoma, testicular
cancer, and acute myeloid leukemia – can be
consistently cured using aggressive
chemotherapy. But these malignant cells seem
to have characteristics that make them
particularly responsive to “treatment.” Just as
invasive species adapt to pesticides, most
cancer cells adapt to therapies. Indeed, the
parallels between cancerous cells and invasive
species suggest that the principles for
successful cancer therapy might be found not in
the magic bullets of microbiology but in the
evolutionary dynamics of applied ecology.
Recent research suggests that efforts to
eliminate cancers may actually hasten the
emergence of resistance and tumor recurrence,
thus reducing a patient’s chances of survival.
The reason arises from a component of tumor
biology not ordinarily investigated: the cost of
resistance to treatment. Cancer cells pay a price
when they evolve resistance to chemotherapy.
For example, to cope with the toxic drugs, a
cancer cell may increase its rate of DNA repair,
or actively pump the drug out across the cell
membrane. In targeted therapies, in which drugs
interfere with the molecular signaling needed for
proliferation and survival, a cell might adapt by
activating or following alternative pathways. All
these strategies use up energy that would
otherwise be available for invasion into non-
cancerous tissues or proliferation, and so
reduce a cell’s fitness.
The more complex and costly the
mechanisms used, the less fit the resistant
population will be. That cancer cells pay a price
for resistance is supported by several
observations. Cells in laboratory cultures that
are resistant to chemotherapies typically lose
their resistance when the chemicals are
removed. Lung cancer cells that are resistant to
the chemotherapy gemcitabine are less
proliferative, invasive, and motile than their
drug-sensitive counterparts.
Although resistant forms are commonly
found in tumors that haven’t yet been exposed
to treatment, they generally occur in small
numbers. This suggests that resistant cells are
not so unfit that drug-sensitive cells completely
out-competed them, but that they struggle to
proliferate when both types are present.
5
Controlling
cancer might
be easier than
curing it
Our models show that in the absence of
therapy, cancer cells that haven’t evolved
resistance will proliferate at the expense of the
less-fit resistant cells. When a large number of
the sensitive cells are killed, say, by aggressive
therapies, resistant types are able to proliferate
unconstrained. This means that high doses of
chemotherapy might actually increase the
likelihood of a tumor becoming unresponsive to
further therapy.
So, just as the judicious use of pesticides
can be used to control invasive species, a
therapeutic strategy designed to maintain a
stable, tolerable tumor volume could improve a
patient’s prospects for survival by allowing
sensitive cells to suppress the growth of
resistant ones.
To test this idea, we treated a human
ovarian cancer, grown in mice, with conventional
high-dose chemotherapy. The cancer rapidly
regressed but then recurred and killed the mice.
Yet when we treated the mice with a drug dose
continuously adjusted to maintain a stable tumor
volume, the animals, though not cured, survived
for a prolonged period of time.
Designing therapies to sustain a stable
tumor mass rather than eradicate all cancer cells
will require a long-term strategy that looks
beyond the immediate cytotoxic effects of any
one treatment. Researchers will need to
establish the mechanisms by which cancer cells
achieve resistance and what it costs them. They
will also need to understand the evolutionary
dynamics of resistant populations, and design
strategies to suppress or exploit the adapted
characteristics.
I am not suggesting that cancer
researchers should abandon their search for
ever-more-effective cancer therapies, or even for
cures. However, it may be time to temper our
quest for Ehrich’s magic bullets and recognize
the cold reality of Darwin’s evolutionary
dynamics. Medicine’s goal of a glorious victory
over cancer may need to yield to recognition
that an uneasy stalemate may be the best we
can achieve.
IMO FACULTY MEET THE FACULTY
IMO currently has 4 faculty associated with it, Alexander “Sandy” Anderson, Bob Gatenby, Bob
Gillies and Kasia Rejniak. The short biographies below show more info on each of them and their
roles at Moffitt.
Sandy Anderson, PhD is co-director of the Integrated Mathematical Oncology (IMO) department
and Senior member at Moffitt Cancer Center. Dr. Anderson performed his doctoral work on hybrid
mathematical models of nematode movement in heterogeneous environments at the Scottish Crop
Alexander Research Institute in Dundee, UK. His postdoctoral work was on hybrid models of tumor-induced
Anderson angiogenesis with Prof. Mark Chaplain at Bath University, UK. He moved back to Dundee in 1996
where he worked for the next 12 years on developing mathematical models of many different aspects
of tumor progression and treatment, including anti-angiogenesis, radiotherapy, tumor invasion,
evolution of aggressive phenotypes and the role of the microenvironment. He is widely recognized as
one of only a handful of mathematical oncologists that develop truly integrative models that directly
impact upon biological experimentation. His pioneering work using evolutionary hybrid cellular
automata models has led to new insights into the role of the tumor microenvironment in driving tumor
progression. Due to his belief in the crucial role of mathematical models in cancer research he moved
his group to the Moffitt Cancer Center in 2008 to establish the Integrated Mathematical Oncology
department.
Bob Gatenby, MD is the chairman of the department of Radiology and co-director of the
Integrated Mathematical Oncology at H. Lee Moffitt Cancer Center. He joined Moffitt in 2008 from the
Robert
University of Arizona where he was Professor, Department Radiology and Professor, Department of
Gatenby
Applied Mathematics since 2000. Bob received a B.S.E. in Bioengineering and Mechanical Sciences
from Princeton University and an M.D. from the University of Pennsylvania. He completed his
residency in radiology at the University of Pennsylvania where he served as chief resident. Bob
remains an active clinical radiologist specializing in body imaging. While working at the Fox Chase
Cancer Center after residency, Bob perceived that cancer biology and oncology were awash in data
but lacked coherent frameworks of understanding to organize this information and integrate new
results. Since 1990, most of Bob’s research has focused on exploring mathematical methods to
generate theoretical models for cancer biology and oncology. His current modeling interests include:
1. the tumor microenvironment and its role in tumor biology. 2. evolutionary dynamics in
carcinogenesis, tumor progression and therapy. 3. information flow in living systems and its role in
maintaining thermodynamic stability.
Bob Gillies, PhD is vice chair of Radiology and director of research imaging at Moffitt. He
Robert
received his PhD in Zoology from University California, Davis in 1979 and did post-doctoral work on
Gillies in-vivo Magnetic Resonance Spectroscopy with Robert Shulman, first at the Bell Labs (Summit, NJ)
and then at Yale University. He joined the faculty at Colorado State University as an Assistant
Professor of Biochemistry in 1982. He moved to the University of Arizona as an associate professor
with tenure in 1988 to establish a research program in biomedical MR spectroscopy, which over the
years has grown to include biomedical MRI. He relocated to the Moffitt in 2008 as part of a major
investment in radiology and imaging research. Bob has received numerous local, national and
international awards for his teaching and research, including the Furrow award for innovative teaching
(U. Arizona), the Yuhas award for radiation oncology research (U. Penn), a TEFAF professorship (U.
! Maastricht) and the distinguished Basic Scientist award from the Academy for Molecular Imaging..
The vision for the Moffitt Imaging Institute ate to develop new applications to diagnose, predict and
monitor therapy response using noninvasive imaging. This work spans a breadth from molecular and
chemical work, to animal studies and to human clinical trials and patient care. Personally, he is
Kasia principal investigator on four NIH grants dealing with tumor imaging and tumor physiology.
Rejniak Kasia Rejniak, PhD is assistant member at Moffitt. Dr. Rejniak performed her doctoral work on
the mechanics of growth of a trophoblast tissue at Tulane University under the supervision of Lisa
Fauci. Her postdoctoral work has centered around the development of a single-cell-based numerical
technique for modeling the growth and development of non-homogenous tissues and multicellular
organisms at the Mathematical Biosciences Institute, Ohio State University. Subsequent work at
Dundee University, UK with Dr. Anderson led to the development of the IBCell (Immersed Boundary
There are currently 4 main faculty model of a Cell) model to understand the mechanics of the formation of epithelial acini. A unique
within or associated with the IMO. aspect of the computational models she develops is their ability to accurately represent morphological
There are also 4 post docs and and biomechanical properties of cells and in particular how these properties differ in cancer versus
many other researchers, including normal. As part of the group brought from Dundee in 2008, she is also very passionate about
clinical faculty, directly involved in integration and sees the IMO as a unique opportunity to fully realize her own computational lab driven
the IMO activities. by experimental and clinical data.

6
MEET THE POST DOCS IMO SOFA
The diversity of interests of the 4 postdocs that are currently employed by the IMO is precisely
what drives the integrated research that we carry out. Getting to know the group and there interests is
one of the reasons for this newsletter and hopefully will stimulate further collaborations both within
and outwith Moffitt. We currently have funds for 3 other positions (see the back page) so this list will
grow but here are the current team:
David Basanta, PhD is a postdoctoral fellow at the Integrated Mathematical
Oncology (IMO) department. He got his undergraduate degree in computer
science from the University of Oviedo (Spain) with a thesis on information
processing and, after a rather brief stay in industry, performed doctoral work on
evolution inspired computing at the department of mechanical engineering at
King's College London (University of London, UK). After his PhD, his work shifted
to the study of the evolutionary dynamics of cancer, first at the Technical
University of Dresden (Germany) and eventually in Sandy Anderson's group (now at Moffitt).  David
uses mathematical tools such as Cellular Automata and Evolutionary Game Theory to study how the
interactions between tumour cells and other tumour cells and with the tumour microenvironment drive
the evolution towards potentially more aggressive cancers. His work has provided novel insights on
the role of homeostasis as a set of mechanisms that need to be disrupted during carcinogenesis, and
on competition and cooperation's effect on the progression of cancers like glioma and prostate.

Edward Flach, DPhil I arrived recently in Tampa but am feeling integrated

already! I came because the ideology of the group is to apply mathematical
modeling to practical problems in biology. The other benefit is to be surrounded
by actual biologists and even real doctors! This gives the kind of insight that I've
never had access to before (and hopefully plenty of hard data to follow). I came
from Dresden, Germany most recently where I was working on developmental
biology with Andreas Deutsch and Andy Oates. I used the cellular Potts model,
which I am now applying to tumour modelling, with a focus on stromal interaction. Before Germany I
was in Bloomington, Indiana. There I was looking at models of biochemistry with Santiago Schnell:
investigating enzyme action. This style of model is proving useful for understanding the effect of drug
application on cell cultures. My doctorate in Philip Maini's group in Oxford was looking at spatial
pattern formation with John Norbury. I was interested in travelling wave invasions of pattern. This
exploration will give a foundation to a model for predicting clinical progression.

Ariosto Silva, PhD is a research scientist at the Imaging and Integrated

Mathematical Oncology (IMO) departments. He got his undergraduate degree in
computer engineering from the Instituto Tecnologico de Aeronautica (2000,
Brazil) with a thesis on development of e-commerce applications in multiple tiers
(presentation, control and business logic). He did his undergraduate internship at
Motorola (1998, Brazil) developing embedded applications and at Accenture
(2000, Brazil) as a technology consultant in banking industry. After a traineeship
in Portugal Telecom (2001, Portugal) developing web based applications for mobile phone account
management, he spent 3 years at Gemalto (former Schlumberger Sema, 2001-2004, France) working
with security of electronic transactions.  His PhD comes from the University of Campinas (2008, Brazil)
in the department of Genetics and Molecular Biology with the thesis entitled "A computational
approach for simulation of biological processes: tridimensional simulation of tumor metabolism and
development".  His recent work has focused on the progression and mechanisms of resistance to
therapy in Multiple Myeloma, a rare incurable disease where hematologic cancer cells proliferate and
take control of the bone marrow. His goal is to use computational models fed by in vitro experiments
and clinical specimens to predict optimized forms of therapy by combining drugs in “evolutionarily
enlightened” protocols.

Tedman Torres, PhD obtained his undergraduate degree in physics from

Sonoma State University, California.   There he spent time assisting in A place to relax, read, debate...
experiments relating to Near-Field Optical Microscopy.   Following this, he Its only a compact little love seat but
pursued doctoral work at Arizona State University where he worked on has been the center piece for many
experimental and theoretical aspects of Fluorescence Correlation Spectroscopy.  discussions and late night grant
His doctoral degree was completed there in the application of Stochastic marathons we’ve come to realize this
Process Theory to Fluorescence Correlation Spectroscopy.  His current work is in sofa is a truly integral part of IMO.
developing a model of drug penetration into cancerous tissue.

77

THE ECOLOGY & EVOLUTION OF CANCER
It might not seem intuitive, but a small albeit
growing number of people found interesting
parallels between ecosystems as studied by
ecologists (yes, think of the Savannah or the
Amazon rain forest or a Coral reef) and tumors.
The idea of viewing cancer from an ecological
perspective is not just about presenting old facts
in a new light but, fundamentally, means that we
cannot just consider cancer as a collection of
mutated cells but as part of a complex balance
of many interacting cellular and
microenvironmental elements. This perspective
means that tissues should be seen as
sophisticated ecosystems in a homeostatic
equilibrium that cancer cells can disrupt.
Therefore, as convenient as it would be for
cancer biologists to study tumor cells in
isolation, that makes as much sense as trying to
understand frogs without considering that they
tend to live near swamps and feast on insects.
Suddenly a frog’s sticky tongue makes much
more sense when you consider how convenient
it is to have one of those if you want to catch
flies. Suddenly it makes sense that a cancer cell
that is close to a blood vessel and is capable of
producing Vascular Endothelial Growth Factors
can benefit from co-opting endothelial cells to
grow its very own vasculature and obtain
nutrients and oxygen.
An ecosystem is made of individuals
(plants, animals, bacteria, independent cells,...)
and the environment they inhabit (water, soil,
oxygen, nutrients,...). The success of an
individual in surviving (and procreating), which is
what matters at the evolutionary level, depends
on how well it competes (for the existing
resources) and cooperates (to produce new
ones) with other individuals in the same, or
different, species. Even a simplified ecosystem
should showcase the interdependence of
species and how important the interactions
between them are. In a stable ecosystem the
number and types of interactions between
species does not change significantly over time,
leading to a dynamic equilibrium of species and
individuals known as ecological homeostasis.
A lake ecosystem: it can remain in equilibrium for long periods of time
before a disruption sets the ecosystem evolving in a different direction.
Species that are viable in a homeostatic
ecosystem are not necessarily viable in a
different one, or in the same one if homeostasis
is disrupted.
The local environment is an important
factor, not only in traditional ecosystems but also
in cancer. This idea dates back to the late 19th
century with Paget's well-known seed-soil
hypothesis [1] which suggests that in order to
understand metastases, the soil (the site of a
metastasis) is as important as the seed (the
metastatic cells). It is beginning to be accepted
that cancer is not just a genetic disease but one
in which evolution plays a crucial role [2]. The
implications are that tumor cells evolve, adapt to
and change the environment in which they live
(which includes other cellular species). The ones
that fail to do so will eventually become extinct.
The ones that do, have a chance to invade and
metastasize. The capacity of a tumor cell to
adapt to a new environment will thus be
determined by the environment and the other
cellular species from the original site, to which it
has already painstakingly adapted.
Adaptation is  thus a critical process in any
system subject to Darwinian evolution, and
cancer is no exception [3]. Although it's role in
Cancer has recently started to be explored, the
full implications have yet to impact the cancer
research community at large. Tumor cell
adaptation to a complex environment like a
tissue ecosystem not only means that finding the
roots of the disease got a whole lot more
challenging (as it is not restricted to the role of a
few genes) but this view also opens new routes
to stop or even reverse cancer progression [4].
In most cases the ecosystem maintains a
dynamic balance or homeostasis from which it
can be disrupted by certain events (such a
invading species, drought, or a fire).
Homeostasis is also a crucial feature of
normal body tissues (those in which cancer has
not been initiated). Evolution selects for
homeostatic organisms that are capable of
recovering from environmental and genetic
insults [5]. The normal form and function of most
tissues (defined by the integration of multiple
cellular, extracellular, chemical and physical
signals/constraints) is to maintain a homeostatic
balance and carry out the role they are required
to perform. Homeostasis loss is traditionally
seen as a key initial step on the route to cancer
development [6]. At its simplest tissue
homeostasis is the balance between cell
proliferation and apoptosis such that the tissue
architecture and function remains constant. It is
no accident that disruptions in these processes
are considered as key features of oncogenic
transformation. Fortunately, there are multiple
mechanisms that regulate these processes and
actively ensure homeostasis maintenance,
8
BY DAVID BASANTA &
SANDY ANDERSON
m a i n l y t h ro u g h t h e re g u l a t i o n o f b o t h
proliferation and apoptosis. These mechanisms
fall into the two broad camps of cellular (e. g.
cell-cell adhesion, cell-ECM adhesion), and
environmental (e.g. metabolic factors, growth
factors, stroma) although there is a great deal of
feedback between these camps with changes in
one driving the other. Therefore to escape
homeostatic control mutant cells need to
significantly modify their baseline phenotypes
and effectively ignore environmental signals. This
will be profoundly influenced by both cellular (in
terms of phenotypic traits such as cell adhesion)
and environmental heterogeneity (in terms of
metabolite levels and stromal communication)
and the feedback between them. The cellular
heterogeneity represents an intrinsic variability
that may be driven by genetic or non-genetic
means but provides the means for homeostatic
disruption. This heterogeneity further
emphasizes the need to understand interactions
that occur within the cancer ecosystem i.e.
between cells and between cells and their
environment.
Given the complexity of the homeostatic
process that emerges from the interactions
between individuals and their environment in an
ecosystem, how can we hope to understand,
never mind cure, cancer? Fortunately for us
mathematical oncologists, theoretical ecologists
have already developed a number of tools that
can be used to study ecosystems, and these
tools are suitable for both big and small
ecosystems.
One tool that is ideal for this is game theory
(GT). Interestingly GT was initially introduced to
understand human and sociological behavior.
The idea is that one can study games in which
the outcome affecting a player depends, not only
on the strategy used, but on the strategies
employed by the other players. A key aspect is
that a strategy to play a game is not good or bad
considered in isolation but only when compared
with the strategies employed by other players: it
is the interactions between the players that
matter. John Maynard Smith pioneered the use
of this tool to study evolutionary dynamics in
ecosystems. This is known as evolutionary game
theory (EGT). The GT assumption that players
have to be rational is, paradoxically, better suited
to the individuals in an ecosystem than to
humans playing either games in economics or
war. The force of natural selection keeps
ecosystem denizens focused on optimizing the
bottom line: reproduction. In the games studied
by evolutionary game theoreticians, individuals
compete for available resources using a variety
of strategies, that is, by presenting different
features and behaviors that can affect their
chances of survival and reproduction. These
features and behaviors, known as the phenotypic

Parasitism: Parasitic wasp cocoons attached to a caterpillar.
strategy, determine the winners and losers of the
evolutionary race. Simple mathematical analysis
using EGT can be used to investigate the
evolutionary dynamics. If some equilibrium is
achieved then this could form the foundation for
homeostasis.
One crucial lesson from EGT for potential
anti-cancer therapies, is that focusing on
indiscriminately destroying as many cancer cells
as possible is not necessarily the smartest thing
to do. In EGT, the long term (equilibrium)
outcome of a game depends on the interactions
between the players, not on the size of the
population. A treatment based exclusively on
removing cancer cells is likely to have only a
temporal effect as in most cases the original
number of tumor cells will eventually be restored
and exceeded. A more effective alternative would
be based on changing the way cells interact with
each other and their environment which would
affect their fitness and thus, potentially, drive
tumor evolution towards less aggressive cell
types or at least to a stable coexistence that
would be less harmful to the patient [7].  The ecosystem view is, ultimately, a holistic
Another potential application of EGT
emerging from the cancer-ecosystem viewpoint
is the study evolutionary dynamics leading to the
emergence of cooperation [8]. A common
misunderstanding about evolution is that the
survival of the fittest means that only the
strongest and meanest survive. But nature is
abundant with examples of inter and intra
species cooperation. The trick is that cooperation
can only emerge within the constraints of
selection, so it can only be sustainable when
everybody (or their genes) benefits. Which is not
to say that all parties should benefit equally.
EGT is particularly useful at studying the
interactions between the players, how those
affect tumor evolution (as in Darwinian evolution),
and how evolution might lead to or away from
homeostatic equilibrium. However, they do not
incorporate space, individual based models (IBM)
do consider both space and time explicitly and
treat each  cell as a distinct entities, offer and
ideal methodology to integrate some features of
EGT within a spatial framework. Specifically they
can incorporate detailed descriptions of the
individual (tumor cell, fish, fox etc) defining its
behavior (migrate, reproduce, die etc) in a given
context (Savannah, lake, muscle tissue etc).
IBMs therefore capture the spatial and temporal
variation that characterizes real ecosystems
allowing us to explore the robustness of key
homeostatic mechanisms.  Moreover, they have
been extensively used by the modeling
community to look at many different biological
systems [9] focussing on how individuals and
their interactions collectively drive different
evolutionary outcomes.
Traditionally the ecological perspective is
firmly grounded at the scale of the phenotype (a
fox, fish, rabbit etc) and essentially ignores
anything below this scale. However, it tends to
be more encompassing at the phenotype scale
and embraces all the different players of the
ecosystem. In contrast with this perspective, the
cancer biology view is very much centered on the
genetic and molecular scales for which there is a
wealth of data. Whilst this provides a solid
foundation to work from, this data is unbalanced
due to the poorly quantified phenotypic-scale.
This imbalance is the result of the dominance
and success of reductionism in cancer research.
Reductionism is undoubtedly responsible for the
exquisite level of understanding of the several
genes and pathways that are involved in tumor
initiation and progression in a variety of tissues.
Unfortunately both of these approaches have
limitations but also have their own strengths that
in fact compliment one another. Ideally we want
to unify this biological-gene-centric view with the
ecological-phenotype-centric view, however,
experimentally this is difficult if not impossible,
without the aid of theoretical approaches
discussed above. In fact, IBMs can explicitly
bridge the genotypic-phenotypic scales [10-12].
one that sees cancer progression as a process
that emerges from the interactions between
multiple cellular species and interactions with the
tumor microenvironment. An ecosystem may be
either under homeostatic control or in
evolutionary driven escape. These states have
intriguing implications for invasion and
metastasis. Are metastatic cells the ones that
represent the best and most adapted cells at the
primary site? Or, on the contrary, does
metastasis and invasion represent the only
alternative for the less successful phenotypes,
capable of escaping the primary site but unable
to compete with better adapted ones locally? 
May it only be a by-product of tumor cells
acquiring the abilities to move and detach from
the main body of the tumor? Is it the result of
cooperation or competition? Regardless of the
answer to this question, an ecological
interpretation of cancer would predict that
metastasis will occur to sites in which the tumor
cells will have a better chance of survival and
colonization. This will depend not only on  the
9
distance from the primary site or on the
availability of lymphatic or blood vessels but also
on the suitability of the new site for colonization.
Since these cells are likely to be reasonably
adapted to specific environmental conditions. A
secondary site that somewhat resembles key
features of the primary one while providing the
metastatic cells with nutrients and room for
growth will always be a more likely target for a
secondary tumor.
The timing for an ecosystemic view of
cancer could not be better: with the development
of high throughput automated microscopy the
ability to gather substantial amounts of cellular
information is becoming a reality. With this new
information the cancer ecosystem is becoming
more complete and therefore theoretical
oncologists will have a better understanding of
the key phenotypic strategies and mechanisms
of interaction that tumor cells, and other
relevant  cells employ. Clearly this means we are
more likely to be successful at producing models
that are both holistic (taking into account the
multiple scales at which cancer takes place) and
quantitative (in which model parameters and
predictions can be compared with experiments)
i.e. qolistic approaches [13].
The heart of the matter is that an ecological
view of tumors does not invalidate but
complements and builds upon  decades of
cancer research and undoubtedly this will lead to
a better understanding of the biology of cancer
and to new and improved therapies. If we may
use the old analogy but framed slightly
differently: we need to properly understand the
trees (e.g. every leaf, twig and branch) before we
can understand the forest but we cannot afford
to ignore the forest because the trees are so
interesting on their own.
1. Paget, S. (1889). Lancet 1889; 1:571-3.
2. Crespi, B. and K. Summers (2005). Trends Ecol Evol 20: 545-52.
3. Anderson, A. R. A., A. M. Weaver, et al. (2006). Cell 127: 905-15.
4. Gatenby, R. A., A. S. Silva, et al. (2009). Cancer Res 69: 4894-903.
5. Basanta, D., M. Miodownik, et al. (2008). PLoS Comp Biol 4: e1000030.
6. Hanahan, D. and R. A. Weinberg (2000). Cell 100(1): 57-70.
7. Gatenby, R. A. (2009). Nature 459(7246): 508-9.
8. Axelrod, R., D. E. Axelrod, et al. (2006). Proc Natl Acad Sci 103:13474-9.
9. Anderson, A. R. A., Rejniak, K.A. & Chaplain M.A.J. (2008) MBI Book.
10.Mansury, Y., M. Diggory, et al. (2006). J. Theor. Biol.238: 146-156.
11.Basanta, D., H. Hatzikirou, et al. (2008). Eur. Phys. J. B 63: 393–397.
12.Gerlee, P. and A. R. A. Anderson (2008). J. Theor. Biol. 250: 705-22.
13.Anderson, A. R. and V. Quaranta (2008). Nat Rev Cancer 8: 227-34.
Symbiosis. Both the bee & flower derive benefit from their interaction.
BIG CITY SLUMS AND TUMOR INVASION
BY ARIOSTO SILVA
In this article we compare two
phenomena: tumorigenesis and the
development of slums in big cities, and
propose that not only are the rules that control
their existence similar but also that the
strategies used to eradicate them are
equivalent and as such can we learn lessons
A similar mechanism is found in the
from one problem to resolve the other.
Slums are a grave problem in big cities in
underdeveloped and developing countries. In
2007 in São Paulo, the biggest city in Brazil,
there were approximately 2,000 slums with a
total population of more than 400,000 families
living in sub-human conditions. Besides the
social problems of this population, deprived of
minimum sanitary conditions, slums are also a
safe haven for organized crime and drug
dealers. Slums gradually grow by engulfing
neighborhoods of the city whose real-state is
downgraded by the proximity with them.
Tumors are believed to be created by the
relentless replication of genetically unstable
cells that, through mutations and selection
from the microenvironment, acquire a set of
phenotypes that allow them to invade healthy
tissue, promote angiogenesis and colonize new
regions of the host and create new tumors [1,
2], eventually reaching a state of tumor burden
that is fatal to the host.
Both phenomena, slums and tumors,
often develop in the periphery of the host
(carcinomas develop from epithelial tissue
separated from the host by basement
membrane while slums have their origin in the
outskirts of towns where real state is less
expensive) where resources are limited and
uncontrolled growth leads to gradients of
resources and harsh conditions.
Both systems invade by “trashing” their
surroundings: tumors invade healthy tissue by
both degradation of the extracellular matrix and
by causing death of healthy cells; it is known
that tumors constitutively metabolize glucose
anaerobically producing lactic acid [3, 4] even
in the presence of oxygen. It has been
proposed that this glycolytic phenotype could
be a mechanism through which tumors
intoxicate their surroundings in order to kill
healthy tissue and make room for new tumor
cells [4].
periphery of growing slums: a wave of
devaluation of real state moves outwards of the
slum propagated by criminality which imposes
a “bad reputation” on the neighborhood,
scaring the residents away and leaving room
for new tenants from the slum periphery or
from outside of the system.
Solid tumors are often avascular during
the early steps of tumorigenesis and are only
able to promote angiogenesis as they achieve
a critical mass. The fragile infrastructure of
slums is no different from solid tumors: as one
progresses into the settlement, the roads
become narrower until cars cannot travel,
which considerably reduces efficiency of law
enforcement. This lack of law enforcement and
a minimum infrastructure for the survival of the
slums is similar to what happens in solid
tumors. On one hand poor perfusion prevents a
faster growth of the tumor but on the other
hand it protects the tumor by preventing the
action of the immune system, chemotherapy
and radiotherapy by limiting diffusion of drugs,
inducing quiescence in hypoxic tumor cells and
by generating a heterogeneous tumor
microenvironment that confers a greater
robustness to therapeutic attack [5].
We have discussed some aspects on how
carcinomas and slums develop in a similar
manner, notably by uncontrolled population
growth in an area at the edge of the host/city
with poor infrastructure but also with small or
no interference from immune system/law
enforcement, as is the case with carcinomas
which are separate from immune system by a
basement membrane.
Both systems appear to be robust to
brute force attacks (toxins and drugs in cancer,
and law enforcement and eviction in slums) not
only because these approaches cause higher
side effects in the “host” than in the target but
also because the forces that promoted the
initial development of these systems remain
unchanged (genetic instability and
microenvironment-imposed selection for
cancer, and social inequality in slums) and thus
will promote regrowth of the original system or
similar systems in other areas.
10
We propose that the most promising
strategies for eradicating and preventing
carcinomas and slums are those that target the
forces that promote their emergence. For
carcinomas these strategies would focus on
intratumoral pH normalization, use of glucose
inhibitors, use the minimum amount of therapy
necessary to arrest tumor growth and delay
patient relapse, and finally assess tumor
response to therapy in a closed-loop approach.
For slums, whose emergence is due to a
considerable mass of poor people, the most
promising approach would be to invest
resources into bringing this share of the society
into more equal conditions, which can be
achieved by full-time public education with
meals and recreational activities in order to
keep the children away from one environment
permeated by violence, drugs and poverty.
Work laws that ensure minimum wages and
social programs to provide credit to families to
finance homes are also more immediate
actions. Finally, the problem of slums in big
cities will never be solved if the flow of
migrants from poorer underdeveloped regions
of the same country remains. It is important
thus that such an action for reduction of social
disparities happens country-wide.
As a final note, we would like to stress
that even though slums carry within criminality
and major social and public health problems,
they only exist and grow because of the initial
advantage of cheap labor they offer to the
richer population of the cities. An interesting
point is that in carcinomas the cells that
develop as tumors are exactly those that are
isolated in the periphery of the host and
considered as “expendable”.
1. Goldie JH: Drug resistance in cancer: a perspective. Cancer Metastasis
Rev 2001, 20:63-68.
2. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
3. Gatenby RA, Gillies RJ: A microenvironmental model of carcinogenesis.
Nat Rev Cancer 2008, 8:56-61.
4. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ: Acid-mediated
tumor invasion: a multidisciplinary study. Cancer Res 2006,
66:5216-5223.
5. Kitano H: Cancer robustness: tumor tactics. Nature 2003, 426:125
WORKSHOPS
Its been a busy start to the 2009 for the
IMO with two major meetings being co-
organized by our members. An MBI workshop
and a three part SIAM symposium both dealing
with in silico models of cancer but with their
own distinct focus.
MBI Workshop: Cancer Development,
Angiogenesis, Progression, & Invasion
The Mathematical Biosciences Institute
(MBI),is an institute dedicated to the
application of mathematics to biology with the
goal of enhancing both research and education
to foster the growth of an international
community of researchers in this new field.
Co-organized by Kristin Swanson and
Sandy Anderson this workshop was based on
the premise that a deeper understanding of
cancer requires scientists willing to
communicate and interact extensively across
disciplinary boundaries. By inviting a truly
interdisciplinary team of scientists to attend as
well as a shared platform for both experienced
modelers, state-of-the art experimentalists and
MBI
Cancer
Workshop
organizers
Ohio
clinician-scientists to present their work
covering every scale of cancer growth.
Each day of the workshop, consisted of 3
primary speakers split between experimental,
mathematical and imaging such that the
experimentalist presented the biological
problem, a mathematical modeler described
modeling approaches and a imaging specialist
described the type of data available for model
validation and development. Other attendees
were invited to present posters at the poster
session and every day one poster was chosen
to give a short presentation to the group.
Each day was broadly themed with
“snow emergency” (see pic above) that
focuses on cancer development,
led to a very impromptu take over of the
angiogenesis, progression, invasion and
holiday inn meeting facilities (where most of the
treatment. We deliberately left 30 minutes after
participants were staying) where the talks
every presentation for discussion which really
proceeded as planned.
caused the whole workshop to be a hive of
For further information regarding the
discussion with each talk leading to extended
workshop, including participants, abstracts and
debates between the interdisciplinary audience
some talks that were presented can be found
and the speaker. This created a vibrant and
at the following link:
exciting atmosphere that really made the whole
http://mbi.osu.edu/2008/ws4description.html
workshop far more successful than we had
hoped.
An interesting aside is that the MBI had to SIAM Symposium: State of the art
close halfway through the meeting due to a in Computational modeling of
Cancer
This three part symposia was aimed at
bringing together all of the key computational
modelers in the Cancer field to discuss the
diversity of new techniques that have recently
been deployed and/or developed. Co-
organized by Kasia Rejniak and Sandy
Anderson at the SIAM Conference on
Computational Science and Engineering.
One of the participants called this
minisymposium "a family reunion" - we actually
really liked this interpretation. We invited 12
scientists, from USA and abroad, working on
different aspects of cancer modeling to share
there scientific experience and results. Thanks
Yi, Andreas, James, Sasha, Heiko, Bruce,
David, Yangjin, Zhihui, Fang for coming.
The minisymposium covered many
aspects of cancer - tumor initiation,
p ro g re s s i o n , a g i o g e n e s i s , m e t a s t a s i s ,
avascular/vascular tumor growth, and cancer
treatment. Techniques presented included
continuous models, various types of individual-
cell based models, Monte-Carlo simulations,
game theory and fluid-dynamics approach.
11

SIAM symposium - Continued
Each of the three IMO members presented
their current work with Kasia opening the 1st
session and Sandy closing the 3rd and final
session. It proved to be a very successful
meeting - so much so that Kasia and Sandy
decided to put together a special issue of the
IMA Journal Mathematical Medicine & Biology.
This will be a double bumper issue and will
collate the recent work of all who attended.
IMO SEMINARS
A WEEKLY SEMINAR WHICH BRINGS TOGETHER THE WHOLE
IMO AND ANYONE ELSE INTERESTED IN SYSTEMS RESEARCH
The first Integrated Mathematical Oncology
seminar, on Thursday September 4th 2008,
gathered together the only five existing
members, speaker included, i.e. the core of the
mathematical modeling group: Bob, Sandy,
To celebrate our move from Scotland to
Florida, we invited our minisymposium
speakers and a few other friends for dinner in
a very cosy Italian restaurant called La Loggia
located in Downtown Miami. It was not only a
nice culinary experience but a challenging one.
We learned that half of the German population
(at least those present at the table) speaks
fluent Norwegian! And we had a lively
discussion-competition to determine what
Kasia, David and Ariosto who gave a
talk on "Adaptive Therapy: an
alter native cancer treatment".
Attendance has increased significantly
when the Molecular and Functional
Imaging group, headed by Bob Gillies,
moved in to town. Moreover, we can
(Vanderbilt)
proudly announce that some of our
invited speakers have enjoyed the
presenting to
friendly but brainstorming atmosphere
of IMO seminars so much, that they
have became affiliates of the IMO and join us
every Thursday at lunch time to actively
participate in both questions and discussion.
Many local Moffitt scientists have given
talks summarizing their research interests and
experimental approaches, and discussed with
us possible areas where mathematical/
computational modeling approaches could be
useful. This has fortunately led to the initiation of
several new collaborations within Moffitt.
We have also hosted a few outside
speakers, including both collaborators and
12
temperature has the same numerical value in
C and F. Well, it took a few approximations and
actually solving one linear equation to find out
that it is -40 :o)
For further information regarding the
workshop, including participants and abstracts
of the talks that were presented, can be found
at the following link:
http://www.siam.org/meetings/cse09/
Presenting our
work at the SIAM
meeting in Miami.
Members of the
IMO: Kasia Rejniak,
Sandy Anderson
and David Basanta
(Left to Right).
Simon
Hayward
IMO
visiting guests from many different disciplines:
mathematicians, experimentalists, image
scientists, radiologists, physicists,
pharmaceutical scientists, pathologists and
clinicians.
To see a list of the past, present and future
speakers please look here: http://
www.moffitt.org/imo/seminars. If you are
interested in participating or presenting an IMO
seminar please contact our seminar organizer
Kasia Rejniak (kasia.rejniak@moffitt.org).
BOOK BY IMO MEMBERS
The “Single-Cell-Based Models in Biology and Medicine” book
in the eyes of its editors Sandy Anderson & Kasia Rejniak
Sandy Anderson and Kasia Rejniak: The
book we have edited together with Mark
Chaplain has been recently published by
Birkhauser-Verlag in the Mathematics and
Biosciences in Interaction (MBI) series. It
contains 12 chapters from leading authors in the
field of single-cell-based computational models
that can be applied in various areas of biology
and medicine, including development,
morphogenesis, tumoriogenesis, blood clotting,
vascularization, tissue folding and cell
chemotactic and haptotactic movement.
Kasia: It is fascinating to watch live cells
under the microscope, to see how they move,
divide and interact with one another. As a
biomathematician, I was always interested in
making computational models that allow for
simulations of cells and cell processes on the
computer screen. It turns out I was not the only
one.
Sandy: Indeed, mathematical modeling of
biological phenomena is not a new trend. One
may trace modeling of tumor growth to the work
of Archibald Hill from 1928 in which the author
uses mathematical approaches to study how the
diffusion of dissolved substances through cells
and tissues determines cell metabolic
processes. However, these early mathematical
models use a purely continuous approach and
represent tumors as well mixed masses of cells
that respond to external cues in an averaged
manner. Whilst these models are able to capture
the tumor structure at the tissue level, they fail
to describe the tumor at the cellular level.
Kasia: So, the development of single-cell-
based models was a natural way to overcome
the limitations of continuous models.
Sandy: Yes, to adequately describe
complex spatio-temporal processes that occur
in multi-cellular organisms, a class of models is
required that simultaneously takes into account
differences between individual cells as well as
their ability to communicate and interact with
one another and their environment. Single-cell-
based models form a framework that allows for
the explicit incorporation of different properties
of individual cells, but at the same time enables
all cells to act together as one collective body.
This leads ultimately to more biologically
realistic models of heterogeneous tissues and
multi-cellular organisms and allows for a better
understanding of the principles underlying the
complex biological processes occurring during
the formation, growth and maintenance of multi-
cellular bodies.
Kasia: We noticed that over the last few
years several biomathematicians and
biophysicists have been working on different
computational models in which cells are
represented as individual entities. These models
employ very different computational
approaches: Monte-Carlo simulations, energy
minimization techniques, volume conservation
laws, solutions of the equations of motion for
each individual cell or for each point on
the cell membrane. They also differ in “We hope
the level of detail that defines the cell that readers will
structure and subsequently differ in the
enjoy this book as
much as we have
number of individual cells that the enjoyed working e s s e n t i a l f o r b u i l d i n g a n d
model can incorporate. So, the on it” understanding good predictive
existence of numerous mathematical
mathematical models.
models dealing with individual cells brought us
Kasia: Right, mathematical models will not
to the idea of putting together a collection of
eliminate biological experiments but instead will
papers where different computational models
help motivate them by generating hypotheses
are described by their authors.
and determining the key factors and processes
Sandy: Therefore, one can use the book to
that need to be tested. To build a mathematical
survey what is new in modern mathematics,
model of a cell, we have to make it much
because very different mathematical and
simpler than in reality by taking into account
computational techniques are used to define the
only the most important features, but we also
range of models included in our book. In some
want to represent differences between individual
of them cells are represented as points on the
cells as well as their ability to communicate and
lattice, in others as small spheres or ellipsoids,
interact with one another and their surroundings.
or they have deformable shapes and contain
Single-cell-based models are ideal for these
elastic boundaries filled with fluid. If one wants
purposes and allow for a more realistic
to focus on mechanical properties of cells, there
representation of biological tissues and multi-
are models that capture that level of detail but
cellular organisms as they can capture the
at the expense of limiting the number of
principles underlying the complex biological
cells the model can handle. If on the other hand
processes.
one wants to model tumor growth, then millions
Sandy: And therefore, we would like to
of cells may need to be represented and
address this book equally to scientists already
therefore considering the cells more simply as
modeling multi-cellular processes and to
single points may be more appropriate.
students starting their research in the field of
Kasia: Moreover, the book is accompanied
mathematical biology to give them a flavor of
by a DVD containing simulation movies that
the different techniques that they can use in
show all discussed models in action! They are
their studies. We asked our contributing authors
applied to a quite diverse set of problems, such
to include a detailed description of their
as tumor growth, limb development, blood
particular model and an extensive review of
clotting, vascularization, cell chemotactic
suitable biological and medical applications.
movement, development of Dictyostelium
And, of course, all simulation movies of the
discoideum, tissue folding or the formation of
presented models and applications are on the
epithelial layers.
DVD!
Sandy: And on top of that, numerous
Kasia and Sandy: So, we hope that the
applications presented in the book are
readers will enjoy using this book as much as
accompanied by experimental results and
we have enjoyed working on it.
images, since continued interactions with
experimentalists working on cellular systems is
13
COMPUTATIONAL IMAGES FROM IMO RESEARCH

Here we present a small selection of the images

generated using the mathematical and computational models
that we are developing within the IMO. Aesthetically
interesting and visually diverse they represent many different
aspect of cancer, including initiation, growth, angiogenesis,
invasion and treatment. The visual representation of in silico model output is an important aspect of
IMO as it drives much of the communication between the multiple disciplines that interact with us. To
paraphrase the old analogy: a picture speaks of... a thousand cubic millimeters! The spatial variation
that occurs in both cancer and its immediate microenvironment are of great interest to the IMO as we
believe that this heterogeneity is what promotes tumor development and inhibits treatment.
Understanding how variations in tissue density, oxygen distribution, drug concentration, and stroma
interact with and regulate tumor cell heterogeneity is a central question were are interested in.
Spatial variation however, is only one part of this picture the other is temporal dynamics. Many
of the images shown here have animated counterparts that dynamically represent the time evolution
of the development/growth/treatment process often from a single initiating cell. Both the spatial and
temporal dynamics of cancer are natural outputs of in silico models, which are often difficult to
obtain with the same detail or frequency form in vitro or in vivo systems. Quantification of these
dynamics and calibration with experimentally measured snapshots via imaging will be a cornerstone
for model validation.
We are currently developing both graphically rich and interactive simulation tools for several of our computational models such that our
experimental colleagues can have their own hands on in silico experience. Eventually, these tools will be available online for all to use and hopefully
facilitate further collaboration and integration.

14
CAN YOU BUILD ME A MODEL PLEASE?
BY SANDY ANDERSON
One of the most common responses that
IMO receives when we try to initiate
collaborations is either that in silico modeling is
far too simple to produce anything informative
or it has some magical property that solves
complex problems without any experimental
input. These two extremes highlight a real lack
of understanding that we must address
directly, after all we are the strangers in a
strange land. The schematic on the right
represents an over simplified attempt to
explain how we can build cancer models
together. It does not encompass all possible
scenarios and we are not constrained by only
this approach.
The single most important aspect of
developing mathematical models is the
motivation i.e. what question do we want to
answer? In the context of cancer this might be
one specific to a given type or might be
relevant to all cancers. Often finding the
question (or the right question) is the biggest
hurdle to start a collaboration. Critical to
defining the question, however, is the dialogue
- we need to talk to each other, perhaps
several times. This dialogue really is where the
common language begins to develop, allowing
us to tease out the key variables and core
processes of the system and how best to
represent them theoretically. This reduces the
complexity of the model and aids in the
subsequent understanding of the results,
however, its worth pointing out that its natural
to always want to add more complexity. Thats
why the integrated approach is so important,
the biological-mathematical dialogue should
converge on a minimal model.
Minimal models make for simpler
visualization and parameterization. There are
then some technical aspects that need to be
addressed in terms of the precise modeling
approach to be used, how it will be solved and
presented - this is where the IMOs diversity
becomes important. The different backgrounds
and interests of the group ensure we take the
best approach, and visualization is something
we take great pride in (see page 12).
It is important to realize that what sets In
silico models apart from other useful
quantitative approaches (such statistics or
i n f o r m a t i c s ) i s m e c h a n i s m . We a r e
fundamentally interested in understanding why
certain outcomes occur. By integrating the
relevant biological processes within our
theoretical framework we can generate
testable predictions and hypothesize novel
mechanisms. Vital to this is model
parameterization (and validation) which can
only be achieved via experimental testing and
observation. In silico model driven
experimentation and imaging are precisely why
we believe being integrated within Moffitt will
be beneficial.
15
Having accurate experimental
measurements of the variables and processes
that are driving the system will allow for much
more accurate model predictions. It will also
highlight the model limitations and where
refinements need to be made. Having a fully
parameterized model that is sufficiently refined
will allow us to make predictions of the tumor
growth dynamics, how it will respond to
different treatments and how best to optimize a
given treatment. Ultimately, this means that we
can tailor in silico models to a specific patient
and make predictions directly relevant to that
patient.
Hopefully his will lead to in silico models
becoming an integrated part of treatment. The
schematic loop below, shows how data based
on analysis of the current patient state (e.g. via
biopsies, imaging) can parameterize models to
make predictions regarding cancer growth and
treatment that can be tested experimentally
before being applied to the patient. This should
result in tailored treatments that are optimized
for the cancer of this patient. This optimization
can continue with subsequent analysis and
repeats of the whole loop. The resulting
therapy will be by definition adaptive to the
changing needs of the patient.
This will, however, take time. We are
constrained by the experimental and clinical
data that we can obtain. Also, the resolution
and scope of this data will dictate to what
degree we can validate the in silico model
results. We are also constrained by the level of
complexity we want to incorporate into our
models, the trade-off between understanding
and sophistication is difficult to balance. There
are multiple modeling approaches at our
disposal and they cover a wide range of
resolution and scale. Choosing the
appropriate in silico approach (or combination
of approaches) should be driven by both the
question and the experimental system to which
it will be validated against. This further
emphasizes the need for integration:
experiments should drive models and models
should drive experiments. This feedback
hopefully converging on novel insights into our
understanding of cancer growth and critically
the development of novel treatments.
Issue 1

The
Ever
LAST WORD FROM THE EDITOR
Growing from IMO members and I’d personally like to thank David

IMO
Basanta, Bob Gatenby, Kasia Rejniak and Ariosto Silva for their
Moving to Moffitt from a mathematics department in
articles and last but not least Edward Flach for his creative flare
Dundee, Scotland seemed like a monumental task. There was
on the numerous schematics throughout.
always going to be a transitionary period and dealing with the
I’d like to end the newsletter on a positive note - the good news is
personal issues that a move of this scale presents. There is no denying it
that we’ve been fortunate enough to secure funding from two major NCI
was difficult at times and could have went smoother. One of the main
programs, the new Physical Sciences in Oncology (PSOC) program and
sticking points was the fact that we are mainly a computational group
the Integrative Cancer Biology program (ICBP). Both of these programs
and therefore needed very different computational facilities. Thankfully,
support the application of theoretical and computational models to
this issue has been directly addressed with the updated Moffitt cluster
cancer research. Clearly this is what IMO already does and so we are
and better support for our Mac centric world. Its worth stating however,
grateful to be part of them! This should certainly keep IMO busy for the
that even though its only been just over a year and a half, IMO feels like
next 5 years or so!
home. Moffitt has made us feel welcome and we’ve already made
Enjoy the rest of 2010, and look for issue 2 next year!
friends and collaborators. As we develop over the coming year, we
Sandy Anderson (Editor).
hope to integrate further with Moffitt, building new collaborations and
working in new areas. Since we have recently outgrown our space in
MRC, we’re looking forward to moving into our new space in SRB -
specially refurbished to enhance the collaborative nature of our research.
We’re HIrINg
This is the first issue of the IMO newsletter, and I hope you’ve •Several Post DOC PosItIoNs are
found it interesting. I realize thats its probably unusual to produce this avaIlable NOW!
type of document but I see this medium as the perfect opportunity to let •MathematIcIaNs, PhysIcIsts or
anyone interested know we are here, what we are doing and where we computer scIeNtIsts
are going. I’d be happy to receive any feedback, both negative and •please CoNtact US!
positive, on the current issue as well as ideas for future content. This www.moffitt.org/Imo/jobs
issue would not have been possible without the numerous contributions

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