Basement membrane is a dense, highly cross-linked form of extracellular matrix that surrounds most tissues. During development and immune surveillance, specialized cells acquire the ability to breach basement membrane to disperse and traffic to sites of infection and injury. The cell invasion program is misregulated during many diseases, including asthma, arthritis, multiple sclerosis, and pre-eclampsia. The inappropriate acquisition of invasive behavior also underlies the spread of cancer, which accounts for 90% of all cancer- related deaths. Understanding how cells invade through basement membrane is thus of great importance to human health. Cell invasion involves dynamic interactions between the invading cell, the tissue being invaded, and the basement membrane separating them. Owing to an inability to recapitulate these complex interactions in vitro, and the challenge of experimentally examining invasion in vivo in vertebrates, the mechanisms underlying cell invasive behavior remain poorly understood. Anchor cell invasion in C. elegans is an experimentally accessible in vivo model of cell invasion that uniquely combines subcellular visual analysis of cell-basement membrane interactions with powerful forward genetic and functional genomic approaches. Using these strengths, our work will characterize a newly identified cellular structure-the invasive protrusion, a specialized membrane domain that both degrades and physically displaces basement membrane during invasion. We will also determine how secretion of the basement membrane structural protein laminin by the invading anchor cell facilitates invasion. Most metastatic tumors overexpress laminin, and we expect this work to have wide relevance to understanding cancer progression. Our studies have also unexpectedly revealed that the anchor cell can invade basement in the absence of matrix metalloproteinases (MMPs) by physically displacing the basement membrane. This finding might explain why inhibition of MMPs in clinical trials of metastatic cancer patients failed. Our work will determine how the anchor cell alters its invasion mode and investigate an increased requirement for mitochondrial generated ATP to compensate for the loss of MMPs. These findings will begin a new research area in energy requirements during cell invasion and inform better approaches to target invasion with MMP inhibitors. Finally, our work will characterize a nascent transcriptional regulatory network that specifies invasion, thus addressing the crucial question of how cells are programmed to be invasive. These integrative studies spanning specialized cellular invasive machinery, basement membrane remodeling and transcriptional regulation are relevant to NIH's mission as they will lead to a deep understanding of the fundamental biological process of cell invasive behavior, thus allowing the development of better therapeutic strategies to limit invasion in human diseases such as cancer.
Cell invasion through basement membrane plays pivotal roles in numerous cell migrations in development and immune cell trafficking. This behavior is also co-opted in many human diseases, most notably during the spread of cancer. Our proposed work will elucidate how cells are programmed to be invasive, and dissect the specific cellular and molecular machinery that allows cells to penetrate basement membrane barriers. These studies will advance our understanding of the fundamental mechanisms underlying cell invasion and generate new therapeutic strategies to block this behavior in human diseases such as cancer.
