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Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin Related Protein 2/3 Complex Activity and Invadopodia Function Steven Michael Markwell Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actinbinding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. While cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown. In this dissertation we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Although overall cancer incidence rates are declining across the United States, the incidence of head and neck squamous cell carcinoma (HNSCC) continues to increase within the Appalachian region. To better understand the underlying factors leading to disproportionate outcomes, our group has established an Appalachian-specific HNSCC patient tissue cohort from surgically-resected tumors. This cohort represents all HNSCC stages, lesion types and morphologies, as well as cases that contain human papillomavirus (HPV) and/or tobacco and alcohol use. Moreover, we have generated several patient derived xenografts (PDXs) from these tissues, allowing further cellular, biochemical and preclinical therapeutic evaluation. Utilization of PDX tumors from this cohort will allow examination of critical steps in the development and potential treatment of invasive, metastatic, and recurrent Appalachian-associated disease. Matched patient and PDX sample availability enables personalized medicine and co-clinical trials aimed at reversing this Appalachian cancer health disparity and ultimately improving regional HNSCC patient care.