The overarching theme of our application is to quantify the impact of cancer cell heterogeneity in tumor growth and treatment resistance. It logically extends results from the previous funding period, pointing to phenotypic heterogeneity as key determinant of progression and invasion. We will consider heterogeneity with respect to phenotypic traits (Proliferation, Motility and Metabolism), in the ICBP-43 breast cancer cell line panel and in drug resistant breast, or radiation responsive lung, cancer cell lines. Trait heterogeneity will be quantified primarily by high-content automated microscopy and image processing. Between cell lines, trait variability will be compared as averages and distribution shapes. Within a cell line, ceil-to-cell variability (presumably non-genetic) will be represented as subpopulations by statistical modeling, e.g., bayesian information criteria and clustering algorithms. To estimate adaptability, we will measure trait variation in response to perturbations mimicking tumor microenvironment conditions. This large dataset (3 traits in >50 lines under >10 perturbations) will be input to mathematical and computational predictive models, tracking the fate of individual cancer cells and the microenvironment in space-time during tumor growth. With the experimental component, this suite of theoretical models forms a Center "Backbone" deployed towards three Projects. Project 1 will quantify adaptive advantage in cancer progression by incorporating cell trait heterogeneity data into mathematical and computational models that exploit evolution dynamics and game theory concepts. Project 2 will measure impact of trait heterogeneity and fitness cost in the rise of breast cancer resistance to first- and second-line drugs (doxorubicin, hormone therapy and HER2 tyrosine kinase inhibitors). Project 3 will attempt to improve and/or predict outcomes of radiation treatment in lung cancer cell lines by coupling experimentally defined radio-phenotype heterogeneity to predictive models. Hypotheses/predictions from Projects 1-3 will be validated in vitro and in mouse tumors, by iteration loops of experimentation and theory. Finally, we will continue education/outreach efforts, e.g., hands-on cancer modeling workshops, to attract physical and biological scientists, especially the brightest of the new generations.
Though central to cancer progression, phenotypic heterogeneity is understudied due to its complexity. Our proposal integrates experimentation and theory to quantify the impact of cell heterogeneity in cancer progression, and deploy novel approaches to cancer drug and radiation resistance. By specializing in Cancer Systems Biology at the subcellular, cellular and tissue scales, we will continue to build a much-needed data and modeling bridge between genetic/molecular and clinical/epidemiological scales.
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|Poleszczuk, Jan; Enderling, Heiko (2014) A High-Performance Cellular Automaton Model of Tumor Growth with Dynamically Growing Domains. Appl Math (Irvine) 5:144-152|
|Kim, Munju; Reed, Damon; Rejniak, Katarzyna A (2014) The formation of tight tumor clusters affects the efficacy of cell cycle inhibitors: a hybrid model study. J Theor Biol 352:31-50|
|Scott, Jacob G; Basanta, David; Anderson, Alexander R A et al. (2013) A mathematical model of tumour self-seeding reveals secondary metastatic deposits as drivers of primary tumour growth. J R Soc Interface 10:20130011|
|Hoshino, Daisuke; Branch, Kevin M; Weaver, Alissa M (2013) Signaling inputs to invadopodia and podosomes. J Cell Sci 126:2979-89|
|Bryce, Nicole S; Reynolds, Albert B; Koleske, Anthony J et al. (2013) WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl. PLoS One 8:e64533|
|Rejniak, Katarzyna A; Quaranta, Vito; Anderson, Alexander R A (2012) Computational investigation of intrinsic and extrinsic mechanisms underlying the formation of carcinoma. Math Med Biol 29:67-84|
|Basanta, D; Scott, J G; Fishman, M N et al. (2012) Investigating prostate cancer tumour-stroma interactions: clinical and biological insights from an evolutionary game. Br J Cancer 106:174-81|
|Kam, Yoonseok; Rejniak, Katarzyna A; Anderson, Alexander R A (2012) Cellular modeling of cancer invasion: integration of in silico and in vitro approaches. J Cell Physiol 227:431-8|
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