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journal article·2025-12Open access

MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

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

Advanced Science· Volume 12· Issue 48
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Glycosylation and Glycoproteins Research · Cellular Mechanics and Interactions · Caveolin-1 and cellular processes

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Hepatobiliary Surgery The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

Pancreatic Disease Treatment Center of Xi'an Jiaotong University Xi'an 710061 P. R. China

Department of Anesthesiology & Center for Brain Science The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University Xi'an 710049 P. R. China

Bioinspired Engineering and Biomechanics Center (BEBC) Xi'an Jiaotong University Xi'an 710049 P. R. China

Department of General Surgery Huashan Hospital Fudan University 12 Urumqi Road (M) Shanghai China

Department of Cardiovascular Surgery The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

Department of Vascular Surgery The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

Department of Geriatric Surgery The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

Department of Medical Oncology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 P. R. China

State Key Laboratory of Mechanics and Control of Mechanical Structures Nanjing University of Aeronautics and Astronautics Nanjing 210016 P. R. China

Department of Mechanical Engineering & Materials Science Washington University in St. Louis St. Louis MO 63130 USA

NSF Science and Technology Center for Engineering Mechanobiology Washington University in St. Louis St. Louis MO 63130 USA

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation · Fundamental Research Funds for the Central Universities

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