Cancer Games: Interactive Simulation of the Effect of Resource Limitation on Cancer Somatic Evolution using nanoHUB CompuCell3D
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Abstract
During solid tumor progression, cells gradually acquire the ability to reproduce in ways deleterious to their host, to acquire nutrients and oxygen, to evade the host immune system and eventually, to remodel their environment, invade surrounding tissues and recapitulate their parent tumor organization in metastases. Progression is often regarded as an inevitable sequel of tumor initiation and its genetic and biomolecular bases are widely addressed. Less studied is somatic evolution within solid tumors, which combine rapid heritable mutation and strong selection. Tumor spread is determined by the behaviors of the small fraction of stem-like cells in the tumor, with higher stem-like fractions leading to more aggressive tumors and lower survival. Considering progression from an evolutionary perspective may help explain two apparent paradoxes: 1) Selection is intrinsically undirected, but results in deterministic progression. 2) Chemotherapies, surgery and raditation often result in substantial reduction of tumor mass, but ultimately lead to greater tumor mass and more invasive phenotypes. In this interactive mini-workshop we will use a very simple model of cancer somatic evolution and resource limitation based on one originally proposed by Heiko Enderling (see, e.g. Jan Poleszczuk, Philip Hahnfeldt, Heiko Enderling “Evolution and Phenotypic Selection of Cancer Stem Cells,” PLoS Computational Biology doi.org/10.1371/journal.pcbi.1004025 (2015)). In this game-theoretic model we have a single limiting resource, space to grow; cancer cells which can have either a stem-like (immortal) or somatic (limited number of cell divisions) phenotype, and undirected mutation in the rate of cell growth, fraction of stem cell divisions which give rise to two stem cells rather than a stem cell and a somatic cell (stemness) and the number of times a somatic cell can divide before dying (senescence). In this simple model the fraction of stem-like cells increases in time. We will study how this rate of increase depends on model parameters and show that partially effective treatments can actually result in rapid increase in the fraction of stem-like cells and hence worse outcomes. If time permits, we will also model the situation where the somatic cells protect the stem cells nearby from being killed by a chemotherapeutic agent.
Bio
Dr. Glazier’s research focuses on early embryonic development, developmental and chronic toxicity and developmental diseases, with more than 70 experimental and computational papers on biological development and developmental diseases (including polycystic kidney disease (ADPKD), tumor growth and vascularization, Age Related Macular Degeneration and diabetic retinopathies, somitogenesis and liver toxicity). He leads the collaborative development of the open-source CompuCell3D multi-scale modeling and model-sharing environment and works closely with the EPA, which has adopted CompuCell3D as a core platform for their CompTox computational toxicology program. He actively disseminates both methods and models, with more than 200 invited talks and seminars on modeling and CompuCell3D. He also maintains an experimental effort in microfluidics and optical biochemical microsensors. He has expertise supervising collaborative development of models and in developing workflows integrating models with experimental data, most recently in the area of developmental toxicology. In 2016, he became one of the founding members of Indiana University’s Department of Intelligent Systems Engineering (the first engineering program at Indiana University, Bloomington), which aims to apply advanced computing techniques to understand and control complex natural and engineered emergent systems. Within ISE, he leads the creation of the Bioengineering track, with 8 faculty hires in 2016 and 2017 and novel transdisciplinary BS, MS and PhD syllabi. As founding director of the Biocomplexity Institute at Indiana University, he has extensive experience in model sharing, having led the MSM model sharing Working Group for 2 years and participated extensively in developing multi-cell model specification standards. He was instrumental in more than 10 interdisciplinary biosciences faculty hires at Indiana University in the Departments of Physics and Biology and the School of Informatics. He also led the creation of a new Biological Physics PhD track with an interdisciplinary syllabus and qualifying examination. He has experience organizing large-scale multidisciplinary biomedical research projects and has organized 11 international workshops on Biocomplexity and numerous symposia and panels at major international meetings as well as 11 CompuCell3D User-training workshops and five workshops on model sharing and standards. He has supervised 14 students who have completed PhD dissertations, 21 postdoctoral researchers and 33 high-school and undergraduate researchers.
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