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Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis

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The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors.

Funding

S.M. is supported by Australian Research Council DECRA (DE150101777) and Australian Research Council Future Fellowship (FT180100333) but the project was not funded by the basic science grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. P.T., D.H., S.C.W., M.C.L., and C.V. are supported by NHMRC, Cancer Council NSW, Cancer Australia, Tour de Cure grants, Cancer Institute NSW, ARC Future, Len Ainsworth and Philip Hemstritch Pancreatic Cancer Fellowships, Sydney Catalyst. We thank the reviewers for providing constructive feedback which improved the manuscript significantly.

History

Publication Date

01/12/2021

Journal

Nature Communications

Volume

12

Issue

1

Article Number

3950

Pagination

16p.

Publisher

Springer

ISSN

2041-1723

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.