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Wednesday, April 11 • 4:30pm - 4:45pm
SYMPOSIA-16: Niche Construction in Cancer: Coevolution of Tumor Cells and Their Microenvironment

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AUTHORS: Arig Ibrahim-Hashim*, Robert Gillies, Robert Gatenby, Joel Brown – H. Lee Moffitt Cancer Center

ABSTRACT: Malignant cells in solid tumors export metabolically derived acid into surrounding stroma. This micro-environmental acidification can be viewed as a “niche construction”. As an evolutionary strategy, acid-production benefits the cancer cell by decreasing the fitness of non-adapted competitors. At the scale of the tumor ecosystem, acidity promotes the transition from in situ to invasive and metastatic cancer. However, there are significant costs to being an acid-producing/adapted cancer cell including reduced efficiency in energy production and increased energy demands for survival in low Ph. We suggest exploiting these costs as a novel therapeutic intervention. A spatially-explicit, agent-based model of the associated non-linear dynamics demonstrates that small increases in tumor pH, appropriately timed, can reduce the fitness advantage of the aggressive cancer cell, and maintain a non-invasive phenotype as the dominant population. We tested this in a genetically modified (TRAMP) mouse model of prostate cancer, wherein we could identify two competing cell types: C2 and C3. C2 cells exhibited the properties of the niche construction phenotype with significantly increased aerobic glycolysis, glycolytic capacity, acid production, glucose uptake, and invasion. In contrast, C3 cells retained a near-normal metabolic profile. Adding 200 mM NaHCO3 to the drinking water of TRAMP mice at age 4 weeks increased intra-prostatic pHe by 0.2 pH units and prevented transition from in situ to invasive cancer. In established tumors, an increase of intratumoral pH significantly decreased primary tumor growth and dramatically reduced metastases. Furthermore, using an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were co-injected into the mammary fat pad of mice. C2-like MDA-MB-231 cells dominated in untreated animals but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pH was increased. Our results demonstrate a novel strategy for using perturbations of complex tumor landscapes to steer the system into a less invasive eco-evolutionary trajectory.

Wednesday April 11, 2018 4:30pm - 4:45pm CDT
Grant Park Parlor

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