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Cited by 240Extracellular vesicles in diseaseCellular Mechanics and InteractionsCellular transport and secretion

Stiff matrix induces exosome secretion to promote tumour growth

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Wu, Bin, Liu, Di-Ao, Guan, Lei, Myint, Phyoe Kyawe, Chin, LiKang, Dang, Hien, Xu, Ye, Ren, Jinqi +13 more·2023·Nature Cell Biology
DOI 10.1038/s41556-023-01092-1PMC PMC10351222
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Abstract

Tissue fibrosis and extracellular matrix (ECM) stiffening promote tumour progression. The mechanisms by which ECM regulates its contacting cells have been extensively studied. However, how stiffness influences intercellular communications in the microenvironment for tumour progression remains unknown. Here we report that stiff ECM stimulates the release of exosomes from cancer cells. We delineate a molecular pathway that links stiff ECM to activation of Akt, which in turn promotes GTP loading to Rab8 that drives exosome secretion. We further show that exosomes generated from cells grown on stiff ECM effectively promote tumour growth. Proteomic analysis revealed that the Notch signalling pathway is activated in cells treated with exosomes derived from tumour cells grown on stiff ECM, consistent with our gene expression analysis of liver tissues from patients. Our study reveals a molecular mechanism that regulates exosome secretion and provides insight into how mechanical properties of the ECM control the tumour microenvironment for tumour growth.

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Cited by

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Authors
Wu, B., Liu, D.-A., Guan, L., Myint, P. K., Chin, L., Dang, H., Xu, Y., Ren, J., Li, T., Yu, Z., Jabban, S., Mills, G. B., Nukpezah, J., Chen, Y. H., Furth, E. E., Gimotty, P. A., Wells, R. G., Weaver, V. M., Radhakrishnan, R., Wang, X. W., & Guo, W.
Affiliations
  • University of Pennsylvania (US)
  • Thomas Jefferson University (US)
  • OHSU Knight Cancer Institute (US)
  • Abramson Cancer Center (US)
  • University of California, San Francisco (US)
  • National Cancer Institute (US)
Corresponding author
Guo, Wei
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2023-02-16
Volume
25
Issue
3
Pages
415-424
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-023-01092-1
PMC
PMC10351222
OpenAlex
W4321112406
Cited by
240
References
6
Citations by year
2026: 54 · 2025: 84 · 2024: 74 · 2023: 28
FWCI
21.83
Type
journal article
Language
en
Update notices
correction (2024-02-12)
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
U.S. Department of Health & Human Services | DHHS Office of the Secretary (CA016520, U01 CA250044, BC 010877, BC 010876, BC 010313, R35 GM141832)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
extracellular matrix stiffness, exosome secretion, tumor growth, Akt activation, Notch signaling, tumor microenvironment, mechanotransduction, liver cancer, fibrosis
MeSH terms
Extracellular Matrix, Humans, Neoplasms, Signal Transduction, Proteomics, Exosomes, Tumor Microenvironment

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