Study of the endocytic mechanism of the tumor marker CD166/ALCAM : a new clathrin-independent cargo
(2022)
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- Endocytosis is an essential cellular process required for the uptake of nutrients from the cell environment and the turnover of plasma membrane components(commonly referred as “cargoes”). It regulates fundamental cellular functions as diverse as cell signaling, adhesion, migration, polarity, division, growth or differentiation. In particular, mammalian cells have developed multiple endocytic routes/mechanisms to support the vast array of physiological conditions, functions and cargoes they face. However, while several endocytic mechanisms have been described so far, their biological relevance often remains elusive, especially in pathophysiological contexts such as cancer. In 2016, my lab identified a cell surface cargo whose internalization seemed to rely on a yet to characterize endocytic route: the protein CD166/ALCAM(Activated Leukocyte Cell Adhesion Molecule). CD166 is an immunoglobulin-like protein involved in cell adhesion and migration, which has been linked to cancer progression by numerous studies. This protein has notably received particular attention as a promising target for new immunotherapies. However, virtually nothing was known about its cellular trafficking. In that context, the present thesis aimed at unveiling the molecular machinery that underlies CD166 internalization and that modulates its function at cancer cell surface. Using state-of-the-art microscopy and cell biology techniques, we could show that CD166 is a clathrin- and dynamin-independent cargo internalized via a novel endocytic mechanism that involves the BAR domain protein endophilin-A3 and the extracellular lectin galectin-8. Additionally, we could demonstrate that the actin cytoskeleton and its regulatory GTPase Rac1 dynamically associate with CD166-positive endocytic carriers and that their perturbation strongly inhibits the uptake process. We also provide evidence that microtubules and kinesin molecular motors are required to potentiate the endoA3-dependent endocytosis of CD166. Finally, our data reveal that altering this new endocytic mechanism directly modulates the abundance of CD166 at the cell surface and regulates adhesive and migratory properties of cancer cells.
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Tyckaert, F. (2022). Study of the endocytic mechanism of the tumor marker CD166/ALCAM : a new clathrin-independent cargo. https://hdl.handle.net/2078.5/103370