Project 1: Ionic Modulation of Chromatin in Cancer

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ABSTRACT (PROJECT 1) Intracellular potassium levels play a central role in regulating physiological processes and are generally maintained within narrow limits. Recent studies reveal that aggressive and highly metastatic breast as well as multiple myeloma cancer cells maintain potassium concentrations that are 200-300% higher than matched non-tumorigenic cells. Since the strongest physicochemical interactions involved in reversible chromatin condensation are electrostatic, any perturbations in the ionic environment of the nucleus, such as those driven by a pathophysiological elevation of cellular potassium content, are anticipated to have profound effects on chromatin structure and access to transcriptional machinery. Thus this discovery has global physiological implications. It also has the potential to unify a variety of reports showing that elevated potassium levels suppress cell death signaling pathways, as well as acting on the large number of ion channel proteins known to play a role in cancer progression. In this proposal we test the hypothesis that alterations in intracellular potassium levels alter chromatin structure and nuclear organization and consequently, global gene expression. To address this hypothesis we will develop new physical methods to: a) understand the impact of potassium concentration on chromatin structure at the physical level in tumor cells; b) probe the relationship between elevated potassium and clinical stage and grade of human tumors; and c) test whether this facet of cancer cell physiology can be exploited for the design of new combination chemotherapies. These experiments will be performed across multiple length scales: from intact living cells to isolated nuclei to metaphase chromosomes and finally on nucleosome core particles. Understanding ion imbalances in cancer may allow the repurposing of current FDA-approved agents, such as diuretics that work by modulating intracellular potassium levels, for use in combination with current chemotherapies for cancer treatment. Drug combinations will be tested in several cancers, including glioblastoma, through collaboration with the Patient Derived Xenograph Core using the Core's series of staged and genotyped GBM tumor lines. This project connects directly to the overarching framework of the CR-PSOC “Spatio-Temporal Dynamics of Chromatin and Information Transfer in Cancer” through the study of physiochemical changes in the nuclear environment that are important in cancer progression. Project 1 investigators will address how changes in cellular concentration of potassium impact chromatin condensation and how this contributes to the malignant phenotype. Members of this transdisciplinary team will work in collaboration with Project 3 to determine the extent of chromatin compaction in intact nuclei, and with members of Project 2 to examine the potential roles for potassium accumulation in leukemia. The role of Project 1 in the Center is to resolve key electrostatic features of the cancer cell nucleus and then apply the new insights to understand, and ultimately intervene in disease progression.