Stiff matrix induces exosome secretion to promote tumour growth

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 unknow...

Full description

Saved in:
Bibliographic Details
Published inNature cell biology Vol. 25; no. 3; pp. 415 - 424
Main Authors Wu, Bin, Liu, Di-Ao, Guan, Lei, Myint, Phyoe Kyawe, Chin, LiKang, Dang, Hien, Xu, Ye, Ren, Jinqi, Li, Ting, Yu, Ziyan, Jabban, Sophie, Mills, Gordon B., Nukpezah, Jonathan, Chen, Youhai H., Furth, Emma E., Gimotty, Phyllis A., Wells, Rebecca G., Weaver, Valerie M., Radhakrishnan, Ravi, Wang, Xin Wei, Guo, Wei
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.03.2023
Nature Publishing Group
Subjects
13/51
13/95
14/19
14/5
38/79
45/70
631/67/327
631/80/313/2376
64/60
82/29
82/80
AKT protein
Biomedical and Life Sciences
Cancer
Cancer Research
Cell Biology
Developmental Biology
Exosomes
Exosomes - metabolism
Extracellular matrix
Extracellular Matrix - metabolism
Fibrosis
Gene expression
Humans
Life Sciences
Mechanical properties
Microenvironments
Neoplasms - metabolism
Proteomics
Secretion
Signal Transduction
Stem Cells
Stiffening
Stiffness
Tumor Microenvironment
Tumors
Online AccessGet full text

Cover

More Information
Summary: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. Wu et al. report that a stiff extracellular matrix stimulates the release of exosomes from cancer cells under the control of Akt and Rab8. These exosomes in turn promote tumour growth.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
Bin Wu, Di-Ao Liu, and Lei Guan contributed equally to the work.
AUTHOR CONTRIBUTIONS
B.W., L.G., D.A.L. and W.G. conceived the project and designed the experiments. B.W. (Fig. 1a, 1d, 2a, 3f, 4c, 4e, 4f, Ex. Fig. 1a, 1c–1e), L.G., D.A.L. (Fig. 1f, 2c, 2d, 2k, Ex. Fig. 1b, 1f, 2c, 3b–3c, 4d), Y.X., P.K.M. (Fig. 1e, 1f, 2b, 3e, 6a, Ex. Fig. 3f) purified and characterized the exosomes. B.W., L.G., D.A.L., Y.X., L.C., P.K.M. performed the polyacrylamide gel and cell culture experiments. B.W. (Fig. 3a–d, 4a, 4b, 4d, 6b, 7e, Ex. Fig. 2b, Ex.3a, ), D.A.L. (Fig. 1b, 1c, 2e, 2h, 2i, 2j, 3g, 3h, 7a, 7b, 7c–d, Ex. Fig. 4a–4c), L.G., Y.X., performed western blot analysis. B.W. and L.G. performed the immunoprecipitation (Fig. 4d, 4e, 4f,). B.W. performed the BRET assay, cell proliferation assay, the immunofluorescence (Fig. 2f–g, 3i–j, ), and electronic microscopy imaging. B.W., L.G., L.Ch., T.L., performed the mouse experiments. J.R. performed the GEF assay (Fig. 4g, 4h). H.D. performed the clinical data analysis. G.M. performed the RPPA experiments. B.W., L.G., D.A.L., H.D., Y.X., E.E.F., X.W., W.G. analyzed and interpreted the data. P.A.G. helped with the statistical analysis. B.W. and W.G. wrote the paper. L.G., D.A.L., Y.X., P.K.M., L.Ch., R.G.W., X.W., Y.H.C., R.R., V.M.W. edited the paper. All authors have read and approved the final manuscript.
ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-023-01092-1