MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

This study uncovers a size‐dependent adhesion paradigm, demonstrating that the glycocalyx protein MUC15 suppresses pancreatic cancer progression by attenuating integrin activation, focal adhesion assembly, and YAP mechanotransduction. Integrating computational modeling and experimental validation, the work reveals a mechanical mechanism by which MUC15 constrains metastatic behavior, offering new insights into glycocalyx‐mediated cancer regulation. Abstract Cancer metastasis is governed by physical cues at the cell‐matrix interface, with matrix stiffness, ligand density, and topography established as key determinants. Here, a fourth critical factor in cancer metastasis, the architecture of the cell‐surface glycocalyx is identified. Using MUC15 as a representative small glycoprotein, mathematical modeling and domain truncation experiments are combined to show that glycoprotein size distribution governs integrin adhesion states and metastatic outcomes. MUC15 localizes to focal adhesions and interact with integrins, while larger glycoproteins such as MUC1 are sterically excluded. These physical effects, rather than intracellular signaling, dictate adhesion state transitions: removing MUC15's ectodomain eliminated its anti‐metastatic effects, whereas removal of its cytoplasmic tail has no effect. In in vivo pancreatic cancer models, modulating MUC15 levels controlled metastasis as predicted by the mathematical model. These findings establish glycocalyx architecture as a mechanical regulator of cancer progression and suggest therapeutic strategies targeting glycoprotein size distribution. This study uncovers a size-dependent adhesion paradigm, demonstrating that the glycocalyx protein MUC15 suppresses pancreatic cancer progression by attenuating integrin activation, focal adhesion assembly, and YAP mechanotransduction. Integrating computational modeling and experimental validation, the work reveals a mechanical mechanism by which MUC15 constrains metastatic behavior, offering new insights into glycocalyx-mediated cancer regulation. Abstract Cancer metastasis is governed by physical cues at the cell-matrix interface, with matrix stiffness, ligand density, and topography established as key determinants. Here, a fourth critical factor in cancer metastasis, the architecture of the cell-surface glycocalyx is identified. Using MUC15 as a representative small glycoprotein, mathematical modeling and domain truncation experiments are combined to show that glycoprotein size distribution governs integrin adhesion states and metastatic outcomes. MUC15 localizes to focal adhesions and interact with integrins, while larger glycoproteins such as MUC1 are sterically excluded. These physical effects, rather than intracellular signaling, dictate adhesion state transitions: removing MUC15's ectodomain eliminated its anti-metastatic effects, whereas removal of its cytoplasmic tail has no effect. In in vivo pancreatic cancer models, modulating MUC15 levels controlled metastasis as predicted by the mathematical model. These findings establish glycocalyx architecture as a mechanical regulator of cancer progression and suggest therapeutic strategies targeting glycoprotein size distribution. Advanced Science, Volume 12, Issue 48, December 29, 2025.