| Popis: |
Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance for anti-tumor immunity is ill defined. Besides its role in Wnt/β-catenin signaling, APC regulates cytoskeleton organization, cell polarity and migration in various cells types. Here we address whether APC plays a role in T lymphocyte migration, a key step of anti-tumor immune responses. Using a series of cell biology tools, we measured migration of primary T cells obtained from FAP patients carrying APC mutations. FAP T cells showed decreased chemotaxis through micropores or endothelial cell monolayers. Concomitantly, they presented lower expression of the VLA-4 (α4β1) integrin at the cell surface. Notably, adhesion and migration in micro-fabricated channels were specifically reduced when surfaces were coated with VLA-4 ligands, indicating that defective adhesion could lead to decreased T cell migration. To further dissect the cellular mechanisms underpinning APC-mediated defects, we depleted APC in the CEM T cell line. We found that APC is critical for VLA-4-dependent adhesion, and acto-myosin and microtubule organization in migrating cells. APC-silenced CEM cells preferentially adopt an ameboid-like migration, lacking adhesive filopodia and continuously extending and retracting unstructured membrane protrusions. These findings underscore a role of APC in T cell migration via modulation of integrin-dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only unbalance epithelial homeostasis, driving intestinal neoplasms, but also impair T cell migration, potentially leading to inefficient T cell-mediated anti-tumor immunity. |
