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Article

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

1
Department of Pharmacology, School of Medicine, University of Nevada Reno, Reno, NV 89557, USA
2
Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 597; https://doi.org/10.3390/ijms22020597
Received: 14 December 2020 / Revised: 5 January 2021 / Accepted: 7 January 2021 / Published: 9 January 2021
(This article belongs to the Section Molecular Oncology)
Metastasis accounts for over 90% of cancer-related deaths, yet the mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV-induced proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth. These studies prompt further evaluation of NDPK-mediated EV signaling using targeted genetic silencing approaches. View Full-Text
Keywords: extracellular vesicles; exosomes; purinergic signaling; nucleoside diphosphate kinase; angiogenesis; metastasis; triple negative breast cancer extracellular vesicles; exosomes; purinergic signaling; nucleoside diphosphate kinase; angiogenesis; metastasis; triple negative breast cancer
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MDPI and ACS Style

Duan, S.; Nordmeier, S.; Byrnes, A.E.; Buxton, I.L.O. Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer. Int. J. Mol. Sci. 2021, 22, 597. https://doi.org/10.3390/ijms22020597

AMA Style

Duan S, Nordmeier S, Byrnes AE, Buxton ILO. Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer. International Journal of Molecular Sciences. 2021; 22(2):597. https://doi.org/10.3390/ijms22020597

Chicago/Turabian Style

Duan, Suzann, Senny Nordmeier, Aidan E. Byrnes, and Iain L. O. Buxton. 2021. "Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer" International Journal of Molecular Sciences 22, no. 2: 597. https://doi.org/10.3390/ijms22020597

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