Proteomics

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Small extracellular vesicles promote stiffness-mediated metastasis


ABSTRACT: Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiological matrix stiffness affects the quantity and protein cargo of small EVs produced by cancer cells, which in turn aid cancer cell dissemination. Primary patient breast tissue produces significantly more EVs from stiff tumor tissue than soft tumor adjacent tissue. EVs released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature increased adhesion molecule presentation (ITGα2β1, ITGα6β4, ITGα6β1, CD44) compared to EVs from softer normal tissue (0.5 kPa; soft EVs), which facilitates their binding to extracellular matrix (ECM) protein collagen IV, and a 3-fold increase in homing ability to distant organs in mice. In a zebrafish xenograft model, stiff EVs aid cancer cell dissemination. Moreover, normal, resident lung fibroblasts treated with stiff and soft EVs change their gene expression profiles to adopt a cancer associated fibroblast (CAF) phenotype. These findings show that EV quantity, cargo, and function depend heavily on the mechanical properties of the extracellular microenvironment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Bart Starich  

LAB HEAD: Denis Wirtz

PROVIDER: PXD049019 | Pride | 2024-06-22

REPOSITORIES: Pride

Dataset's files

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RO-CS-LE_201015_WirtzD_BS_F.mzML Mzml
RO-CS-LE_201015_WirtzD_BS_F.mzid.gz Mzid
RO-CS-LE_201015_WirtzD_BS_F10.raw Raw
RO-CS-LE_201015_WirtzD_BS_F25.raw Raw
RO-CS-LE_201015_WirtzD_BS_F5.raw Raw
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Publications


Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiologic matrix stiffness affects the quantity and protein cargo of small extracellular vesicles (EV) produced by cancer cells, which in turn aid cancer cell dissemination. Primary patient breast tissue released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature  ...[more]

Publication: 1/2

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