Oxygen impact on tumor metastasis dormancy and therapy

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Following dissemination from a primary lesion, a few surviving carcinoma cells establish residency in distant sites (micrometastases). Many micrometastases assume a dormant (quiescent) cellular phenotype, characterized by a G0/G1 arrest that may persist years to decades before outgrowth to form clinically evident metastases; these emergent tumors almost inexorably lead to death. Unfortunately, micrometastases often appear to be refractory to therapeutic agents, even ones that show success against the primary tumors from which they derive. This situation is particularly daunting in breast cancer that can li dormant for a decade or more before recurring. Signals from the tumor microenvironment have been shown to play a critical role in maintaining this dormant phenotype on the one hand or facilitating emergence from cellular quiescence on the other. Culture of breast cancer cell lines in a novel all human liver microphysiological system (MPS) our lab employs has been shown to reliably induce cancer cell dormancy. Traditionally, rapidly proliferating cancer cells resort to glycolysis in order to accumulate the massive amounts of metabolic intermediates required for cell division (Warburg Effect). However, the phenotypically dormant cancer cells may exhibit a different metabolic profile, which may be essential to both maintaining quiescence and successful novel treatment approaches. Our foundational model is that dormant micrometastases adapt a low metabolic and proliferative state concordant with chemoresistance and reduced glycolytic flux. We hypothesize that oxygen tension levels will dictate the switch between oxidative phosphorylation and glycolytic metabolism, and thereby impinge on dormancy. This model will be tested by measuring the basal glycolytic and oxidative phosphorylation fluxes of dormant cancer cells by quantifying glucose uptake, glycolytic enzyme expression, and intracellular ATP concentration through cell culture experiments and immunofluorescence. A novel hemoglobin-based oxygen carrier (HBOC) will be introduced to the system to modulate the oxygen tension to which the cancer cells and liver tissue are exposed. Sensitive ruthenium oxygen sensors will be used to determine the oxygen tension to which the cells are exposed and the trans-tissue oxygen gradient to elucidate the impacts of oxygen tension on tumor dormancy phenotype and cell metabolism. Finally, select anti-tumor agents, including the chemo-therapeutics doxorubicin and cisplatin, will be incorporated into the liver MPS to determine whether therapeutic efficacy is dependent on cancer cell metabolic state and concurrently monitor toxicities to the liver tissue. Understanding the influence of oxygen tension on dormant micrometastasis phenotype, metabolism, and treatment susceptibility is expected to yield insights into basic tumor biology and promote translational studies into improving the efficacy of current treatments (drug rescue) and the discovery of novel therapies.