The Role of MK2 on head and neck cancer cell migration, invasion, and metastases - Abstract Cancer metastases is a devastating problem for all cancer patients and both locoregional and distant disease progression is a major cause of cancer related death in head and neck squamous cell carcinoma (HNSCC) patients. A fundamental characteristic of metastases is the ability of a cancer cell to migrate and invade into neighboring tissues or into vessels that distribute them to distant locations. Improving our understanding of this process enables us to devise strategies to halt migration and invasion, improving local therapies such as radiotherapy, and thus cancer control and long-term survival. Our published work shows that MAPKAPK2 (MK2) regulates tumor radiosensitivity and inhibition of MK2 with radiotherapy significantly improved patient derived HNSCC tumor control and overall survival, in vivo. We have identified several MK2 regulated inflammatory and mesenchymal genes that are involved in tumor cell migration and invasion. Recent studies implicate stromal cells within the tumor microenvironment that may contribute to cancer progression and metastases in an MK2 dependent fashion. However, how tumor intrinsic MK2 regulates the molecular switches involved in head and neck cancer migration, invasion, and regional and distant metastases in patients is poorly understood. We hypothesize that HNSCC tumor MK2 pathway activation leads to primary therapy failure through increased loco- regional and distant metastases. We propose to test this hypothesis by focusing on 3 specific aims. Aim 1 will examine how tumor MK2 regulates FAK-ITGβ4 mediated tumor cell migration-invasion. We will use a novel biotin-ligation proximity labeling assay to help us to identify MK2 specific protein-protein interactions. In Aim 2 we will study how radiotherapy is affected by either tumor intrinsic MK2 inhibition (genetic) or inhibition of MK2 in the tumor and its microenvironment (drug). We want to see whether MK2 inhibition can successfully reduce tumor loco-regional or distant recurrence-metastases, in vivo. In Aim 3, we will use a novel microphysiologic system (MPS) capable of using HNSCC patient tumor and stromal cells to successfully reconstruct and grow these cells on a chip, in vitro. We will obtain locally advanced patient HNSCC primary tumor specimens and grow them in our MPS devices to test the ability of a novel MK2 inhibitor (currently under Phase II clinical investigation) to inhibit HNSCC migration and invasion. The culmination of our work will provide a mechanistic understanding of how tumor intrinsic MK2 regulates cancer cell migration-invasion. The work will also assess the impact of MK2 inhibition on locoregional and distant metastases in vivo when sequenced with primary therapy and will provide a pre-clinical window into how a clinical MK2 inhibitor can reduce patient locoregional and distant metastases.
