Attaching to and Crossing Endothelial Monolayers
Leukocyte extravasation is a critical component of the innate immune response, while circulating tumor cell extravasation is a crucial step in metastasis formation. Despite their importance, the mechanisms underlying leukocyte and tumor cell extravasation remain incompletely understood. In this talk, we present a novel imaging framework that integrates microfluidics with high-speed, label-free imaging to study the arrest of pancreatic cancer cells (PDAC) on human endothelial layers under physiological flow conditions. To facilitate analysis of our imaging data, we use a suite of open-source image analysis tools we developed, including ZeroCostDL4Mic and DL4MicEverywhere for deep learning-based labeling and segmentation, TrackMate v7 for enhanced cell tracking, and CellTracksColab for compiling and analyzing tracking data.
Our findings reveal that PDAC cells exhibit variable adhesion strengths and sensitivities to flow, with some cells preferentially arresting at endothelial junctions, similarly to leukocytes. This location provides PDAC cells access to the underlying basal extracellular matrix. PDAC cells also tend to cluster in regions with high CD44 receptor expression on endothelial cells. Both simulations and experimental data suggest that CD44-mediated attachment and localized flow disturbances enhance subsequent cell adherence. Targeting CD44 via siRNA, function-blocking antibodies, or the degradation of its ligand, hyaluronic acid (HA), almost completely abolishes PDAC cell attachment to endothelial monolayers. By combining advanced imaging strategies and developing image analysis software, we are advancing our understanding of cancer cell extravasation.
Short Bio: Guillaume Jacquemet earned his PhD from the University of Manchester, UK, and then carried out postdoctoral training at the University of Turku, Finland. He is currently a K. Albin Johansson Research Professor (FCI) hosted at Åbo Akademi University. His laboratory uses and develops live-imaging and image-analysis methodologies to investigate how cancer cells interact with and respond to their surroundings during metastasis.
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