Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis

Nat Biomed Eng. 2025 Sep 2. doi: 10.1038/s41551-025-01487-5.

Hyun-Kee Min ^# ¹ ² ³, Hongyu Zhao ^# ¹ ² ⁴ ⁵, Alexander Bahcheli ³ ⁶, Peng Pan ⁷ ⁸, Jade Chan ¹ ² ³, Junsheng Chen ¹ ², Esther Low ¹ ², Yuxiao Zhou ⁷, Xian Wang ¹ ² ⁹ ¹⁰, Savo Bajic ⁷, Ran Peng ¹¹, Siyi Wanggou ¹ ² ⁴ ⁵, Qi Yang ¹ ², Robert Du Yang Zhang ¹ ², Leiming Wang ¹², Xiufang Ren ¹³, Haoyue Qi ¹⁴, Yu Shi ¹⁴, Madeline N Hayes ¹ ³, Brian Ciruna ¹ ³, Jüri Reimand ³ ⁶ ¹⁵, Xinyu Liu ⁷ ¹⁶, Xi Huang ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
2 Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
3 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
4 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
5 Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China.
6 Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
7 Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada.
8 Institute of Robotics and Intelligent Systems, Dalian University of Technology, Dalian, China.
9 Department of Mechanical and Materials Engineering, Queen's University, Kingston, Ontario, Canada.
10 Ingenuity Labs Research Institute, Queen's University, Kingston, Ontario, Canada.
11 College of Marine Engineering, Dalian Maritime University, Dalian, China.
12 Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China.
13 Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.
14 Yu-Yue Pathology Scientific Research Center and Jinfeng Laboratory, Chongqing, China.
15 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
16 Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
17 Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. xi.huang@sickkids.ca.
18 Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. xi.huang@sickkids.ca.
19 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. xi.huang@sickkids.ca.
# Contributed equally.

PMID: 40897897 DOI: 10.1038/s41551-025-01487-5

Abstract

Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in the tissue microenvironment. How brain tumour growth alters the conduit of biofluid and impacts FSS-regulated Cancer progression is unknown. Dissemination of medulloblastoma (MB) cells into the cerebrospinal fluid initiates metastasis within the central nervous system. Here, by simulating cerebrospinal fluid dynamics based on magnetic resonance imaging of patients with MB, we discover that FSS is elevated at the cervicomedullary junction. MB-relevant FSS promotes metastasis along the mouse spinal cord. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased motility, cell clustering and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by the mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis.

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