. Epithelial cell behavior is tightly regulated by the surrounding mE. This control is mediated through the coordinated actions of cell-cell adhesion, paracrine/autocrine growth factors and through adhesion to the extracellular matrix. Together, these mechanisms ensure that cells do not proliferate inappropriately or stray from their immediate mE niche. The process of oncogenic transformation and tumor progression entails the escape from these mechanisms, and the evolution ofthe tumor cell population towards phenotypes that allow them to become independent ofthe normal tissue mE. Activation ofthe underlying stromal fibroblasts, leading to the increased production of paracrine growth factors and pro-survival ECM is one way that developing tumors can achieve mE independence. The complexity of the host-tumor interaction in the carcinogenic process lends itself well to integrated experimental/mathematical based approaches, which are designed to handle multiple variables simultaneously. The current project will initially consider the mechanisms which control normal tissue homeostasis and subsequently homeostatic escape by using three different modeling approaches that examine the roles physical constraints, cell-mE interactions and evolutionary dynamics play in carcinogenesis. In the second part we will use novel in vitro organotypic cell culture models to test whether the presence of an activated stroma can provide the second

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-9)
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H. Lee Moffitt Cancer Center & Research Institute
United States
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Gatenby, Robert; Brown, Joel (2018) The Evolution and Ecology of Resistance in Cancer Therapy. Cold Spring Harb Perspect Med 8:
Gravenmier, Curtis A; Siddique, Miriam; Gatenby, Robert A (2018) Adaptation to Stochastic Temporal Variations in Intratumoral Blood Flow: The Warburg Effect as a Bet Hedging Strategy. Bull Math Biol 80:954-970
Ibrahim-Hashim, Arig; Robertson-Tessi, Mark; Enriquez-Navas, Pedro M et al. (2017) Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution. Cancer Res 77:2242-2254
Brown, Joel S; Cunningham, Jessica J; Gatenby, Robert A (2017) Aggregation Effects and Population-Based Dynamics as a Source of Therapy Resistance in Cancer. IEEE Trans Biomed Eng 64:512-518
Perfahl, Holger; Hughes, Barry D; Alarcón, Tomás et al. (2017) 3D hybrid modelling of vascular network formation. J Theor Biol 414:254-268
de Groot, Amber E; Roy, Sounak; Brown, Joel S et al. (2017) Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis. Mol Cancer Res 15:361-370
Gatenby, Robert A; Frieden, B Roy (2017) Cellular information dynamics through transmembrane flow of ions. Sci Rep 7:15075
McFarland, Christopher D; Yaglom, Julia A; Wojtkowiak, Jonathan W et al. (2017) The Damaging Effect of Passenger Mutations on Cancer Progression. Cancer Res 77:4763-4772
Zhang, Jingsong; Cunningham, Jessica J; Brown, Joel S et al. (2017) Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat Commun 8:1816
Zhang, Xiaomeng; Wojtkowiak, Jonathan W; Martinez, Gary V et al. (2016) MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts. PLoS One 11:e0155289

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