Research Center

Arizona Cancer and Evolution Center

Overview

Center Title

Arizona Cancer and Evolution Center

Overall Project Title

Need project title

Center Website

http://cancer-insights.asu.edu/about-ace/

Center Summary

Cancer is an evolutionary and ecological phenomenon driven by the fundamental forces of evolution: mutations, natural selection and genetic drift. It provides a classic example of multi-level selection. At the level of individual cancer cells, selection favors neoplastic proliferation; at the level of the host organism, selection favors cancer suppression. A full understanding of cancer hinges on an appreciation of this fundamental tension. Regulatory mechanisms at the organismal level determine evolutionary parameters at the cell level such as the somatic mutation rate and response to DNA damage. Cancer circumvents those constraints and changes the parameters of cell-level evolution, leading to malignancy and eventual host death. Thus, organismal and cell-level evolution feed back upon each other. To paraphrase Dobzhansky, nothing in cancer biology makes sense except in the light of evolution. This opens an opportunity. We may apply evolutionary and ecological theory to neoplastic progression and response to therapy.

The mission of the Arizona Cancer and Evolution Center (ACE) is to advance our fundamental understanding of cancer and its clinical management through the development and application of evolutionary and ecological models to cancer biology. This mission spans scales from the evolution of cancer suppression mechanisms and cancer susceptibility across species (Project 1) down to the evolution of normal somatic cells (Project 2) and populations of cancer cells (Project 3).

Project 1 will develop models of organismal evolution to predict cancer rates and cancer defenses across species. We will test those predictions using veterinary databases of cancer incidence in over 1,900 animal species, and examine the genomes of 57 mammalian species for evidence of adaptations to the selective pressure of cancer. In addition, Project 2 will test Project 1’s model predictions of cancer defenses in primary cells from those same 57 mammalian species.

Project 2 will also measure the fundamental forces of evolution in normal colonic and small intestine tissue from humans, mice and elephants to address a basic but poorly understood property of cancer: tissue-level differences in cancer susceptibility. Project 3 will develop novel evolutionary and ecological indices, based on models of cell-level evolution in neoplasms from Project 1, to predict long term therapeutic response and patient survival in stage 2&3, chemo-naïve colorectal cancers. These indices will provide, for the first time, a classification system that the community can use to draw distinctions between tumors with different evolutionary dynamics, and thereby provide a foundation for the clinical management of this evolving disease. ACE will support the Cancer Systems Biology Consortium and the growing field of evolution and cancer by providing data, analytical tools, models, workshops, and tutorials to facilitate the use of those resources.

Investigators

Principal Investigators

Carlo Maley

Associate Professor, Arizona State University

Prof. Maley is a cancer biologist, evolutionary biologist and computational biologist, working at the intersection of those fields. His team applies evolutionary and ecological theory to three problems in cancer: (1) Neoplastic progression: The evolutionary dynamics among cells of a tumor that drive progression from normal tissue to malignant cancers, (2) Acquired therapeutic resistance: the evolutionary dynamics by which our therapies select for resistance and how we may be able to prevent or control resistant cancer cells, and (3) the evolution of cancer suppression mechanisms in large, long-lived animals like elephants and whales (a problem called Peto’s Paradox). They use genomic data mining, phylogenetics, computational modeling, as well as wet lab techniques to solve these problems. In all of this work, their goals are to develop better methods to prevent cancer and improve cancer management.

Darryl Shibata

Professor, University of Southern California

After attending UCLA for his undergraduate degree, Dr. Shibata obtained his medical degree from the Keck School of Medicine of USC. After completing his internship training in pediatrics from UC San Diego, Dr. Shibata returned to USC for his residency and fellowship at LAC+USC Medical Center. Currently, Dr. Shibata has clinical appointments at both LAC+USC Medical Center and USC/Norris Comprehensive Cancer Center. In addition to his wide array of responsibilities in the research, education and practitioner capacities, Dr. Shibata sits on the editorial board of the BMC Cancer Journal and the American Journal of Pathology.

Participating Investigators

Athena Aktipis

Assistant Professor, Arizona State University

Athena Aktipis is an Assistant Professor in the Psychology Department at Arizona State University, co-Director of the Human Generosity Project and Director of Human and Social Evolution and co-founder of the Center for Evolution and Cancer at the University of California, San Francisco.  Dr. Aktipis completed her BA at Reed College (Psychology), her PhD at University of Pennsylvania (Psychology) and post-doctoral work at University of Arizona (Ecology and Evolutionary Biology). She is a cooperation theorist, theoretical evolutionary biologist, and cancer biologist who now works at the intersection of these fields.  Dr. Aktipis is the author of the forthcoming book from Princeton University Press “Evolution in the flesh: Cancer and the transformation of life.”

Amy Boddy

Assistant Professor, University of California, Santa Barbara

Amy Boddy is an Assistant Professor in the Integrative Anthropological Sciences Unit at the University of California, Santa Barbara (UCSB) and a Research Associate in the Broom Center for Demography at the University of California, Santa Barbara. Dr. Boddy is a human biologist and evolutionary theorist. Her work uses applications from evolution and ecology to understand human health and disease. She uses a combination of genomics, computational biology and evolutionary theory to understand life history trade-offs between survival and reproduction across different levels of biological organization. One component of her research program examines how environmental cues, such as high extrinsic mortality, may guide resource allocations to cancer defenses and reproduction. Current cancer research topics include comparative oncology, intragenomic conflict, cellular life history trade-offs, and early life adversity and cancer outcomes later in life. In addition to her cancer research, she studies maternal/fetal conflict theory and the consequences of fetal microchimeric cells in maternal health and disease.

Christina Curtis

Assistant Professor, Stanford University

Christina Curtis, PhD, MSc is an Assistant Professor in the Departments of Medicine (Oncology) and Genetics in the School of Medicine at Stanford University where she leads the Cancer Systems Biology Group and serves as Co-Director of the Molecular Tumor Board at the Stanford Cancer Institute. Trained in molecular and computational biology, she received her doctorate from the University of Southern California in 2007 advised by Simon Tavaré, and holds Masters degrees in Bioinformatics and Computational Biology from the University of Southern California and in Molecular and Cellular Biology from the University of Heidelberg, Germany. She has been the recipient of several young investigator awards, including the 2012 V Foundation for Cancer V Scholar Award, the 2012 STOP Cancer Research Career Development Award, a 2016 AACR Career Development Award and was named a Kavli Fellow of the National Academy of Sciences in 2016. Dr. Curtis is the principal investigator on grants from the NIH/NCI, Department of Defense, American Association for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation, V Foundation for Cancer Research and Emerson Collective. She also serves on the Editorial Boards of Breast Cancer Research, Carcinogenesis: Integrative Biology, the Journal of Computational Biology and JCO Precision Oncology.

Paul Davies

Regents Professor, Arizona State University

Paul Davies is a theoretical physicist, cosmologist, astrobiologist and best-selling science author. He has published about 30 books and hundreds of research papers and review articles across a range of scientific fields. He is also well-known as a media personality and science popularizer in several countries. His research interests have focused mainly on quantum gravity, early universe cosmology, the theory of quantum black holes and the nature of time. He has also made important contributions to the field of astrobiology, and was an early advocate of the theory that life on Earth may have originated on Mars. For several years he has also been running a major cancer research project, and developed a new theory of cancer based on tracing its deep evolutionary origins. Among his many awards are the 1995 Templeton Prize, the Faraday Prize from The Royal Society, the Kelvin Medal and Prize from the Institute of Physics, the Robinson Cosmology Prize and the Bicentenary Medal of Chile. He was made a member of the Order of Australia in the 2007 Queen’s birthday honours list and the asteroid 6870 Pauldavies is named after him. His more recent books include About Time, The Origin of Life, The Goldilocks Enigma: Why Is the Universe Just Right for Life?, How to Build a Time Machine and The Eerie Silence: Are We Alone in the Universe?

Pauline Davies

Professor of Practice, Arizona State University

Pauline Davies is an award winning radio science and health broadcaster with an extensive international career.  She spent many years with the BBC’s World Service where her programs reached audiences of tens of millions worldwide.  Her topics ranged from fundamental physics to human origins and she has reported from conflict zones on maternal health and combatant injuries. She continues to make documentaries from across the sciences for public broadcasters worldwide.  Now she collaborates with the Mayo Clinic on a project to help prevent physician burnout, but her main specialization is the dissemination of cancer research. She led the outreach and education component of an NCI Physical Sciences and Oncology Center for 5 years and is excited to work with her talented ACE colleagues in finding new ways to bring fundamental research findings to the science community and the public.

Trevor Graham

Professor, Barts Cancer Institute, QMUL

Professor Trevor Graham leads the Evolution and Cancer laboratory at the Barts Cancer Institute, QMUL in London, UK.  The lab focuses on measuring the dynamics and drivers of somatic evolution in human tissues, particular in the gastrointestinal tract, and tries to use these measures to better predict cancer development risk in premalignant disease, and determine prognosis and optimise treatment regimes in established cancers. His multidisciplinary lab combines expertise in both theory (maths, physics, computer science, evolutionary biology) together with empirical measurement (molecular genetics, histopathology, bioinformatics).

Tara Harrison

Assistant Professor, North Carolina State University

Dr. Tara Harrison is a veterinarian who specializes in zoo animal medicine and the epidemiology of cancer across zoo animal species. She became interested in cancer in zoo animals after diagnosing a lion with T-cell lymphoma and not being able to find information on how to treat it, or what the survival would be for him after treatment. She has since worked on treating numerous zoo and exotic animal species diagnosed with cancer. She, along with Dr. Zehnder, have created escra.org to better discover what types of cancers, their risk factors, and treatments exist in zoo and exotic animals. She has joined up with the ACE colleagues as we are all interested in the prevalence of cancer across zoo and exotic animal species.

Hanna Kokko

Professor, University of Zurich

Hanna Kokko is an evolutionary ecologist and mathematical modeller. Her stay at the Wissenschaftskolleg zu Berlin in 2014 sparked her interest in cancer as a life history problem. She currently runs a research group that focuses on life history questions – such as scheduling of reproduction, reproductive modes (e.g. sex or asex? with or without a male-female dimorphism?), ageing, and dispersal – with the aim of theory building being informed by all life, rather than constrained by the necessarily narrow view offered by a few model species.

Li Liu

Assistant Professor, Arizona State University

Dr. Liu is an assistant professor of Biomedical Informatics and the director of the Bioinformatics Core Facility at Arizona State University. She holds an M.D. degree in Medicine and an M.S. degree in Information System. As a trained clinician and a bioinformatics researcher, she fully appreciates the critical roles genomic medicine and bioinformatics play in advancing precision medicine. By integrating genomic, phylogenetic, population genetic, statistical and machine-learning techniques, Dr. Liu and her research team investigate clinical and molecular signatures of human diseases, and develop novel computational methods to discover biomarkers for early diagnosis and accurate prediction of therapeutic responses for individual patients. Before joining ASU, Dr. Liu helped build and directed the bioinformatics core facility at University of Florida.

Joshua Schiffman

Professor, University of Utah

Dr. Schiffman is a pediatric hematologist-oncologist at Primary Children’s Hospital (PCH) and Huntsman Cancer Institute (HCI) at the University of Utah.  He serves as the Medical Director for the Family Cancer Assessment Clinic, where he cares for children and families with inherited risk for cancer. Dr. Schiffman’s research focuses on the development of pediatric cancer and he runs a translational genomics laboratory to identify which children are at risk for cancer and why.  Dr. Schiffman works closely with epidemiologists, population scientists, and molecular biologists to try to answer this question. Most recently, Dr. Schiffman recognized the power of comparative oncology to advance the field of cancer research. Teaming up with collaborators from across the country, the Schiffman Lab is now actively involved in comparing the genomics and functional biology of different species across the animal kingdom and using this information to generate hypotheses to guide experimental design in cancer research.  Dr. Schiffman holds the inaugural Edward B. Clark, MD Endowed Chair in Pediatric Research.

Andrea Sottoriva

Team Leader, The Institute of Cancer Research, London

Dr Andrea Sottoriva obtained his BSc in computer science from the University of Bologna in 2006 and his MSc in computational modelling from the University of Amsterdam in 2008. While attending his BSc and master’s he worked in neutrino physics at the Department of Physics of the University of Bologna and at the Institute for Nuclear and High Energy Physics (NIKHEF) in the Netherlands as a research assistant. During his master’s he specialised in computational biology and bioinformatics and became interested in mathematical modelling of cancer. This emerging field employs rigorous mechanistic modelling and simulations to understand complex biological systems such as cancer.

In 2012 he completed his PhD in cancer genomics and modelling at the University of Cambridge within the CRUK Cambridge Research Institute, focusing on the integration of computational models with cancer genomic data. After his PhD he conducted postdoctoral research at the University of Southern California within the Norris Comprehensive Cancer Centre, investigating the use of multiple sampling genomic data from human malignancies to understand tumour evolution.

Dr Sottoriva joined the Centre for Evolution and Cancer at The Institute of Cancer Research, London, in 2013, where his research focuses on using multi-disciplinary approaches based on high-throughput genomics and mathematical modelling to understand cancer as a complex system driven by evolutionary principles. The goal of his group is to identify those patient-specific rules that regulate the development and progression of the disease, to inform prognosis and novel therapeutic options that are tailored to the need of the individual cancer patient. He is currently the Chris Rokos Fellow in Evolution and Cancer at the ICR.

Yinyin Yuan

Team Leader, The Institute of Cancer Research, London

Yinyin Yuan is the leader of the Computational Pathology and Integrative Genomics team at the ICR. Her team develops computational approaches to study tumours as evolving ecosystems by fusing digital pathology, bioinformatics and ecological statistics. The research focuses on the emerging concept that tumours are complex, evolving ecosystems with dynamic crosstalk among cancer, immune and normal cells. Studying the complex relationships between cancer cells and their natural habitats allows for development of new and effective therapeutic interventions, analogous to draining the swamps to help eradicate malaria. By combining large-scale digital pathology, machine learning and spatial statistics, her team studies how genetically different cancers grow and spread under selective pressures from the tumour microenvironment.

Ashley Zehnder

Research Scientist/Postdoctoral Fellow, Stanford University

Ashley Zehnder graduated from the University of Florida College of Veterinary Medicine in 2005, completed a small animal medicine and surgery internship at the Animal Medical Center in New York City in 2006 and a 3-year residency in Companion Avian and Pet Exotic Medicine at the University of California-Davis, becoming boarded in Avian Medicine in 2009.  She completed her Cancer Biology PhD in the Khavari Lab at Stanford in 2016, working on novel therapeutic strategies to target altered signaling pathways in epithelial cancers. Since beginning her research training at Stanford, she has pursued interests in cancer biology as well as comparative medicine by maintaining active research interests in both fields.  She spearheaded the Zoobiquity Research Symposium held at Stanford in April 2014 and Stanford One Health symposium in 2016, which brought together veterinarians and human medical researchers to discuss research efforts in infectious diseases, cancer as well as novel animal models of disease. She is also on the Board of Advisors for Stanford One Health. More recently, she has founded a research alliance to bring together medical professionals to pursue research interests relating to cancer in non-domestic species, shedding light on the biology of tumors in these potentially valuable animal models (www.escra.org).  Her current research focuses on building resources and methods to improve sharing of veterinary clinical data across the US as well as developing a tumor database focused on non-domestic species, thereby helping to identify potential novel models of cancer for human and animal research.

Projects

Project 1: Organismal Evolution and Cancer Defenses

PIs: Maley, Kokko, Boddy; Co-Is: Aktipis, Harrison, Zehnder

Cancer has been an important selective pressure for organisms and a great deal of variation in cancer rates exist across species. Why do species vary in their susceptibility to cancer and what mechanisms are responsible for this variation? Life history theory (LHT) may provide an explanation for these differences. LHT is an evolutionary and ecological approach that focuses on organism-level tradeoffs between growth, maintenance and reproduction. Organisms can either live fast and die young, or live slowly and die old, or anywhere in between. Cancer suppression is an important component of building a robust body that can live into old age. Our previous models show that lower levels of cancer defense can be favored by natural selection when there are tradeoffs with traits such as reproductive competitiveness, body size, and longevity. Here we use real life history parameters to predict cancer rates across animals and test the predictions with a highly curated comparative oncology dataset, including animals from major orders of reptiles, birds, fish, amphibians and mammals. Additionally, we will analyze the genomes of mammalian species to identify patterns of selection and mutation in tumor suppressor genes. Our approach combines mathematical modeling, comparative techniques, evolutionary theory, genomic sequencing, molecular evolution, and phylogenetics to study cancer suppression. We are particularly interested in identifying cancer resistant species, discovering how they prevent cancer, and translating that into better cancer prevention for humans.

Life history strategies fall on a continuum from fast to slow, and organisms with a fast life history strategy allocate less energy to somatic maintenance (i.e. cancer defense), while slow life history organism have higher investment in cancer defenses, such as DNA damage sensitivity

Impact: More cancers could be prevented if we better understand the evolution of cancer defense mechanisms and other biological parameters that make humans more susceptible to cancer than other species. We can leverage these findings to develop novel tools for prevention and clinical management of human cancers. Comparative oncology offers a unique opportunity to see how evolution has, over millions of years, led to both cancer defense mechanisms and why certain forms of susceptibility remain.

Project 2: Somatic Cell Evolution in Small Human Replicative Units

PI: Shibata; Co-Is: Graham, Schiffman

This Project will study somatic cell evolution in distinct, small human replicative units (intestinal crypts and tumor glands). The compartmentalization of cells into small replicative units can modify evolution because selection and drift (random cell turnover) is limited to immediately adjacent cells. The advantages of analyzing small replicative units are that experimentally they large enough to measure with conventional methods yet small enough to simulate in detail. Characterizing somatic cell evolution in replicative units can lead to better understanding of tumor evolution because selection or drift first occurs at the cell-cell level.

We will sample multiple colon crypts from different aged individuals and multiple tumor glands from opposite sides of 20 colorectal tumors (adenomas and CRCs). Crypts from different species will also be compared with the human data. For each crypt or gland we will document genetic alterations (whole genome sequencing), epigenetic alterations (ATAC-seq), and expression. Combining epigenetic and genetic evolution is important because phenotypic plasticity can mimic clonal evolution when epigenetic modulation allows a single genome to express multiple phenotypes. This data will be modeled through simulations to better understand somatic cell proliferation (division and death) within small replicative units, specifically to determine whether selection or neutral drift are more common during normal human aging and tumor progression.

This Project will also compare the evolutionary biology of fibroblasts. We will test the predictions of Project 1 for the mutation rates, proliferation rates, apoptosis rates, DNA damage response, and stress responses of early passage, primary fibroblasts from species with a wide variety of life history traits. We will also test for functional differences in cancer associated pathways that have evidence of selection in specific species identified by Project 1.

Project 3: Neoplastic Cell Evolution

PIs: Graham, Yuan; Co-Is: Sottoriva, Liu, Curtis

Cancer is an evolutionary process where a single cell grows into a visible tumor after it has acquired multiple driver alterations. In this Project, we will develop predictive biomarkers for colorectal cancer (CRC) outcomes. The innovation is that the biomarkers will be direct measures of evolution. Such evolution-based biomarkers also provide mechanistic understanding for what aspects of evolution most impact survival. To fully characterize tumor evolution, it is necessary to measure both how tumor cells evolve and the host ecology.

In Aim 1, mutations detected by whole exome sequencing of CRC cohorts with long-term follow-up will be classified as public (clonal) and private (subclonal). CRCs will then be subclassified with a newly developed algorithm that can infer selection (positive, neutral, negative) based on private mutation frequencies, where selection preferentially increases (positive) or decreases (negative) subclone subsets. In Aim 2, we will scan microscope sections from the above tumors, using a unique automated platform that can identify cells and quantify tumor microenvironments with respect to lymphocytes and stromal cells. To determine if host ecological heterogeneity reflects responses to specific tumor subclones, we will overlay private mutation distributions on the same microscope slides.
We will combine tumor evolution and the host reaction into a single evolution-ecology (Evo-Eco) index that summarizes the underlying evolutionary struggle. For example, patients with aggressive tumors (positive selection) and supportive environments are likely to have poorer outcomes relative to patients with tumors under negative selection and repressive environments. We will validate our Evo-Eco index on another cohort of CRCs. If successful, these studies will yield improved CRC predictive biomarkers.

Outreach

PI: Pauline Davies; Co-Is: Aktipis, Paul Davies

The Outreach Unit of the Arizona Cancer and Evolution (ACE) Center will bring together students, researchers, and the general public to consider the evolutionary pathways and ecology of cancer. We have three aims within our Outreach Unit: (1) to integrate and synergize our interdisciplinary team to produce real innovation and ultimately impact the field of cancer research; (2) to connect the Center with the wider Cancer Systems Biology Consortium, other scientists and the public to promote collaboration; (3) to educate the next generation of scientists and communicators in cancer research methods and encourage them to work in integrative teams in order to stimulate new ideas.  We will achieve these aims through a comprehensive program that includes educational courses, online tutorial videos with accompanying monitored discussion boards, seminars, internships and public lectures and also an innovative creative activity – a unique, immersive new media exhibit, based on the work of ACE Center researchers, that visualizes the fundamental forces of evolution: mutation, selection and drift in relation to the ecology of cancer cells. This project will explore the intersection of science, art and technology to promote new ways of imagining scientific concepts. It will be displayed in major public galleries and conferences.

IMPACT: We will stimulate public interest in cancer theory research and educate students, scientists and the public about ACE advances and our drive to understand the nature of cancer and its evolutionary origins.  We will foster research and academic excellence and advance the goals of the National Cancer Institute.