Invasive Protrusion Formation and Damage during Basement Membrane Invasion

Abstract

Basement membranes (BM) are thin, dense layers of extracellular matrix enwrapping most tissues. BM defines tissue shape, mediates tissue connection, and serves as the signaling platform for cellular growth and differentiation. Normally, cell movement across BM is limited, as BM plays the barrier role against random exchange of materials. However, in several developmental and physiological situations like epithelial to mesenchymal transition of neural crest cells and immune surveillance carried out by leukocytes, cells acquire the ability to transmigrate through the surrounding BM. Also, uncontrolled, dysregulated cell invasion is associated with the progression of diseases like fibrosis and cancer metastasis. Since BM has a rigid structure, to breach BM, invasive cells are required to implement specialized strategies including formation of a large invasive protrusion through the BM, which demands large amounts of membrane lipids, is highly stressful to the invading cells, and often results in cellular damage. Here, I use C. elegans anchor cell (AC) invasion as the in vivo model system to investigate invasive protrusion. In Chapter 1, I discuss different methods that invasive cells use to migrate through BM and propose AC invasion as the model system to study invasive protrusion. In Chapter 2, I found that de novo lipid biosynthesis and specialized prenylation machinery in the AC drives the formation of invasive protrusion during BM invasion. In Chapter 3, I revealed that the AC accrues and heals the damage on its plasma membrane (PM) during BM breaching with invasive protrusion and identified the regulators that help maintain the AC PM integrity. In Chapter 4, I explain the significance of the results from my study on expanding our understanding of how invasive cells generate invasive protrusion through lipid synthesis and modification for BM invasion and how invasive cells cope with the stress and injury on their PMs during BM migration. In addition, I discuss about future work that could further add to the current knowledge about invasive protrusion.