Bending the Blueprint: Constricted Migration Effects on Nuclear Architecture in Cancerous and Non-Cancerous Cells

Metastatic cancer cells must be able to deform their nuclei exerting large amounts of forces on it and its contents as they traverse throughout the body to reach a secondary site of proliferation. The forces put on the nucleus during the migration through tight constrictions are enough to alter the 3D genome structure of the cells. But we still do not fully understand what causes these alterations, if the 3D genome could play a role in migration capability, or if all cells experience the same effects and consequences from constricted migrations. The work in this dissertation aims to answer four main questions: what happens to the 3D genome structure as cells pass through constrictions? What, if any, 3D genome profiles can be selected for better constricted migration? What are the similarities and differences between cancerous and non-cancerous cells that experience constricted migration? And lastly, when do changes arise during sequential constricted migrations? Chapter I addresses what happens to the nucleus morphology and 3D genome structures of A375 melanoma cells after they pass through 10 rounds of migration. Chapter IV later focuses within that time frame to determine when the changes to nuclear morphology and 3D genome structures first arise. Chapter II aims to answer the questions of selection vs induction for why some cancer cells within a tumor have better capabilities to be successful at constricted migration. Chapter III then explores how constricted migration is experienced and potentially recovered from in innately migratory, non-cancerous fibroblasts. This chapter details some similarities and more differences between these fibroblasts and our previous cancer data. Overall, these findings suggest that the 3D genome of cancer and non-cancerous cells plays a role in migration efficiency and can be initially selected for or forced to change to become highly migratory, but only in cancerous cells.