title: Simulating Heterogeneous Tumor Cell Populations.
abstract: Certain tumor phenomena, like metabolic heterogeneity and local stable regions of chronic hypoxia, signify a tumor's resistance to therapy. Although recent research has shed light on the intracellular mechanisms of cancer metabolic reprogramming, little is known about how tumors become metabolically heterogeneous or chronically hypoxic, namely the initial conditions and spatiotemporal dynamics that drive these cell population conditions. To study these aspects, we developed a minimal, spatially-resolved simulation framework for modeling tissue-scale mixed populations of cells based on diffusible particles the cells consume and release, the concentrations of which determine their behavior in arbitrarily complex ways, and on stochastic reproduction. We simulate cell populations that self-sort to facilitate metabolic symbiosis, that grow according to tumor-stroma signaling patterns, and that give rise to stable local regions of chronic hypoxia near blood vessels. We raise two novel questions in the context of these results: (1) How will two metabolically symbiotic cell subpopulations self-sort in the presence of glucose, oxygen, and lactate gradients? We observe a robust pattern of alternating striations. (2) What is the proper time scale to observe stable local regions of chronic hypoxia? We observe the stability is a function of the balance of three factors related to O2-diffusion rate, local vessel release rate, and viable and hypoxic tumor cell consumption rate. We anticipate our simulation framework will help researchers design better experiments and generate novel hypotheses to better understand dynamic, emergent whole-tumor behavior.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0002-3378-4513
authors.initials: A
authors.lastname: Sundstrom
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, United States of America.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
authors.affiliation: Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America.
authors.forename: Bud
authors.initials: B
authors.lastname: Mishra
mesh_terms: D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D003198:Computer Simulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D013559:Symbiosis
chemical_list: D019344:Lactic Acid; D005947:Glucose; D010100:Oxygen