MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

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.

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Publication Details

Journal
Advanced Science
Published
2025-10-13
DOI
https://doi.org/10.1002/advs.202513552
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.00
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article

MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

Min Lin, Xinlong Chen, Tian Jian Lu, Yangyang Yue et al.
Advanced Science
Glycosylation and Glycoproteins Research
article

MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

Min Lin, Xinlong Chen, Tian Jian Lu, Yangyang Yue, Yiqun Song, Feng Xu, Zhiping Ruan, Weikun Qian, Simei Zhang, Qinhong Xu, Zeen Zhu, Guy M. Genin, Jin Wang, Qing Li, Yaomin Zhu, Shuai Wu, Jianpeng Li, Hongyuan Zhu, Zheng Wang
article en

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 ScienceVol. 12(48)
Washington University in St. Louis (US), First Affiliated Hospital of Xi'an Jiaotong University (CN), Huashan Hospital (CN), Xi'an Jiaotong University (CN), Nanjing University of Aeronautics and Astronautics (CN)
Openalex Percentile: Top 74%
Glycosylation and Glycoproteins Research
DOIOpen Access PDFOpenAlex
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